Human NK3 receptor-selective antagonist compounds, method for obtaining them and pharmaceutical compositions containing them

ABSTRACT

Compounds of formula (I), a method for obtaining them and pharmaceutical compositions containing them are described. The compounds are useful as human NK 3  receptor antagonists.

This application is a 371 of PCT/FR 96/01416 filed Sep. 13, 1996, now WO97/10211, published Mar. 20, 1997.

The present invention relates to novel selective human NK₃ receptorantagonist compounds for the preparation of drugs useful in thetreatment of psychiatric diseases, diseases of psychosomatic origin,hypertension and, in general, any central or peripheral pathologicalcondition in which neurokinin B and the NK₃ receptor are involved in theinterneuronal regulatory processes, to a method of obtaining saidcompounds and to the pharmaceutical compositions in which they arepresent as the active principle.

Diseases of psychosomatic origin are understood as meaning diseaseswhich originate in the central nervous system (CNS) and havepathological consequences on the peripheral nervous system.

In recent years, numerous research studies have been carried out ontachykinins and their receptors. Tachykinins are distributed throughoutboth the central nervous system and the peripheral nervous system. Thetachykinin receptors have been recognized and are classified into threetypes: NK₁, NK₂, NK₃. Substance P (SP) is the endogenous ligand of theNK₁ receptors, neurokinin A (NK_(A)) that of the NK₂ receptors andneurokinin B (NK_(B)) that of the NK₃ receptors.

The NK₁, NK₂ and NK₃ receptors have been identified in differentspecies. Thus the NK₃ receptors have been identified in the guinea-pig,the rat and the monkey (Br. J. Pharmacol., 1990, 99, 767-773);Neurochem. Int., 1991, 18, 149-165); they have also been identified inman (FEBS Letters, 1992, 299 (1), 90-95).

A review by C. A. Maggi et al. looks at the tachykinin receptors andtheir antagonists and gives an account of the pharmacological studiesand the applications in human therapeutics (J. Autonomic Pharmacol.,1993, 13, 23-93).

The following non-peptide compounds may be mentioned among the specificNK₁ receptor antagonists: CP-96345 (J. Med. Chem., 1992, 35, 2591-2600),RP-68651 (Proc. Natl. Acad. Sci. USA, 1991, 88, 10208-10212) andSR140333 (Curr. J. Pharmacol., 1993, 250, 403-413).

In the case of the NK₂ receptor, the non-peptide selective antagonistSR48968 has been described in detail (Life Sci., 1992, 50, PL101-PL106).

As far as the human NK₃ receptor is concerned, the non-peptide selectiveantagonist(+)-N-[1-[3-[1-benzoyl-3-(3,4-dichlorophenyl)piperid-3-yl]propyl]-4-phenylpiperid-4-yl]-N-methylacetamidehydrochloride, or SR142801, has been described (EP-A-0 673 928; Peptidesand their antagonists in tissue injury, Montreal, Canada, Jul. 31-August3, 1994. Canadian J. Physiol. Pharmacol., 1994, 72 (suppl. 2), 25, Abst.III. 0.9.; Life Sci., 1994, 56 (1), 27-32; British Pharmacol. Society,Canterbury, 1995, Apr. 6-8; Eur. J. Pharmacol., 1995, 278 (1), 17-25;1st Eur. Congress Pharmacol., Milan, 1995, Jun. 16-19).

Patent applications EP 474 561 and EP 512 901 describe neurokininantagonists, more particularly NK₁ or NK₂ receptor antagonists.Pharmacological studies of peptide and non-peptide NK₁ and NK₂ receptorantagonists have shown that their affinities for these receptors, andtheir pharmacological activities, are very dependent on the species;this is very probably the result of small differences in the amino acidsequences, inducing very slight structural variations in these receptorsfrom one species to another (J. Autonomic Pharmacol., 1993, 13, 23-93).Some experimental data, confirmed by pharmacological characterization ofthe compounds forming the subject of the present invention, seem toindicate that a comparable situation exists for the NK₃ receptor. Inparticular, the human NK₃ receptor differs from the NK₃ receptor of therat.

Non-peptide compounds have now been found which have a very strongaffinity for the human NK₃ receptor and a high specificity for saidreceptor. These compounds can be used for the preparation of drugsuseful in the treatment of psychiatric diseases, diseases ofpsychosomatic origin and any central or peripheral diseases in whichneurokinin B and the NK₃ receptor are involved in the intemeuronalregulatory processes.

Very strong affinity for the human NK₃ receptor is understood as meaningan affinity characterized by an inhibition constant Ki which isgenerally less than 5.10⁻⁹ M.

In ligand binding studies, the inhibition constant Ki is defined by theCheng-Prusoff relationship (in Receptor Binding in Drug Research, eds.R. A. O'BRIEN. Marcel Dekker, New York, 1986): ##EQU1## [L]:concentration of the ligand, Kd: dissociation constant of the ligand,

IC₅₀ : concentration which inhibits ligand binding by 50%.

High specificity for the human NK₃ receptor is understood as meaningthat the inhibition constant (Ki) for the human NK₃ receptor isgenerally at least 100 times lower than the inhibition constant (Ki) forthe NK₂ receptor or the inhibition constant for the NK₁ receptor ofdifferent species.

Thus, according to one of its aspects, the present invention relates tocompounds of the formula ##STR1## in which: R₁ is hydrogen;

R₂ is the methyl group;

or R₁ and R₂ together form a group --(CH₂)₃ -- or --(CH₂)₄ --;

Ar₁ is a phenyl which is unsubstituted or monosubstituted orpolysubstituted by a substituent selected from a halogen atom, ahydroxyl, a (C₁ -C₄)alkoxy, a (C₁ -C₄)alkyl, a trifluoromethyl and amethylenedioxy, said substituents being identical or different; athienyl which is unsubstituted or substituted by a halogen atom; abenzothienyl which is unsubstituted or substituted by a halogen atom; anaphthyl which is unsubstituted or substituted by a halogen atom; anindolyl which is unsubstituted or N-substituted by a (C₁ -C₄)alkyl or abenzyl; an imidazolyl which is unsubstituted or substituted by a halogenatom; a pyridyl which is unsubstituted or substituted by a halogen atom;or a biphenyl;

T is a group --CH₂ --; a group --CO--; a group --COO--; or a group--CONR₃ -- in which R₃ is a hydrogen or a (C₁ -C₄)alkyl;

A is a direct bond; a group --(CH₂)_(t) --, in which t is one, two orthree; or a vinylene group;

or --T--A-- is the group --SO₂ --;

Z is an optionally substituted, mono-, di- or tri-cyclic aromatic orheteroaromatic group; and

B is:

i--either a group B₁ of the formula ##STR2## in which J₁ is: i₁ either agroup ##STR3## in which: x is zero or one;

Ar₂ is a phenyl which is unsubstituted or monosubstituted orpolysubstituted by a substituent selected from a halogen atom, a nitro,a hydroxyl, a trifluoromethyl, a (C₁ -C₄)alkyl, a (C₁ -C₄)alkoxy and amethylenedioxy, said substituents being identical or different; apyridyl; a thienyl; a pyrimidyl; or an imidazolyl which is unsubstitutedor substituted by a (C₁ -C₄)alkyl; and

X₁ is a group selected from:

(1) hydrogen;

(2) (C₁ -C₇)alkyl;

(3) formyl;

(4) (C₁ -C₇)alkylcarbonyl;

(5) --(CH₂)_(m) --OR₄ ;

(6) --(CH₂)_(m) --OCOR₅ ;

(7) --(CH₂)_(m) --OCONH--(C₁ -C₇)alkyl;

(8) --O--CH₂ CH₂ --OR₆ ;

(9) --(CH₂)_(n) --SR₇ ;

(10) --CH₂ --S(O)_(j) --(C₁ -C₇)alkyl;

(11) --NR₈ R₉ ;

(12) --(CH₂)_(p) --NR₁₀ R₁₁ ;

(13) --NR₁₂ COR₁₃ ;

(14) --NR₁₄ COCOR₁₅ ;

(15) --(CH₂)_(p) --NR₁₄ C(═W₁)R₁₆ ;

(16) --(CH₂)_(m) --NR₁₄ COOR₁₇ ;

(17) --(CH₂)_(m) --NR₁₄ SO₂ R₁₈ ;

(18) --(CH₂)_(m) --NR₁₄ C(═W₁)NR₁₉ R₂₀ ;

(19) --(CH₂)_(n) --COOR₂₁ ;

(20) --(CH₂)_(n) --C(═W₁)NR₁₉ R₂₀ ;

(21) --CO--NR₂₂ --NR₂₃ R₂₄ ;

(22) --CN; ##STR4## or X₁ forms a double bond between the carbon atom towhich it is bonded and the adjacent carbon atom of the piperidine ring;

in which groups:

m is zero, one or two;

n is zero or one;

p is one or two;

j is one or two;

W₁ is an oxygen atom or a sulfur atom;

R₄ is a hydrogen or a (C₁ -C₇)alkyl;

R₅ is a hydrogen; a (C₁ -C₇)alkyl; a (C₃ -C₇)cycloalkyl which isunsubstituted or substituted by one or more methyls; a phenyl; or apyridyl;

R₆ is a hydrogen; a (C₁ -C₇)alkyl; a formyl; or a (C₁ -C₇)alkylcarbonyl;

R₇ is a hydrogen or a (C₁ -C₇)alkyl;

R₈ and R₉ are each independently a hydrogen or a (C₁ -C₇)alkyl; R₉ canalso be a (C₃ -C₇)cycloalkylmethyl, a benzyl or a phenyl;

or R₈ and R₉, together with the nitrogen atom to which they are bonded,form a heterocycle selected from azetidine, pyrrolidine, piperidine,morpholine, thio-morpholine, perhydroazepine and piperazine which isunsubstituted or substituted in the 4-position by a (C₁ -C₄)alkyl;

R₁₀ and R₁₁ are each independently a hydrogen or a (C₁ -C₇)alkyl; R₁₁can also be a (C₃ -C₇)cycloalkylmethyl or a benzyl;

R₁₂ is a hydrogen or a (C₁ -C₇)alkyl;

R₃ is a hydrogen; a (C₁ -C₇)alkyl; a (C₃ -C₇)cycloalkyl which isunsubstituted or substituted by one or more methyls; a phenyl; a benzyl;a vinyl; a pyridyl; a firyl; a thienyl; a pyrrolyl; or an imidazolyl;

or R₁₂ and R₁₃ together are a group --(CH₂)_(u) --, in which u is threeor four;

R₁₄ is a hydrogen or a (C₁ -C₇)alkyl;

R₁₅ is a (C₁ -C₄)alkoxy;

R₁₆ is a hydrogen; a (C₁ -C₇)alkyl; a (C₃ -C₇)cycloalkyl which isunsubstituted or substituted by one or more methyls; a phenyl; a benzyl;a vinyl; a pyridyl; a furyl; a thienyl; a pyrrolyl; or an imidazolyl;

R₁₇ is a (C₁ -C₇)alkyl or a phenyl;

R₁₈ is a (C₁ -C₇)alkyl; an amino which is free or substituted by one ortwo (C₁ -C₇)alkyls; or a phenyl which is unsubstituted ormonosubstituted or poly-substituted by a substituent selected from ahalogen atom, a (C₁ -C₇)alkyl, a trifluoromethyl, a hydroxyl, a (C₁-C₇)alkoxy, a carboxyl, a (C₁ -C₇)alkoxycarbonyl, a (C₁-C₇)alkylcarbonyloxy, a cyano, a nitro and an amino which is free orsubstituted by one or two (C₁ -C₇)alkyls, said substituents beingidentical or different;

R₁₉ and R₂₀ are each independently a hydrogen or a (C₁ -C₇)alkyl; R₂₀can also be a (C₃ -C₇)cycloalkyl; a (C₃ -C₇)cycloalkylmethyl; ahydroxyl; a (C₁ -C₄)alkoxy; a benzyl; a phenyl; or a (C₁ -C₇)alkylsubstituted by a hydroxyl, a (C₁ -C₃)alkoxy, a phenyl, a carboxyl, a (C₁-C₃)alkoxycarbonyl or a carbamoyl which is unsubstituted or substitutedby one or two (C₁ -C₇)alkyls;

or R₁₉ and R₂₀, together with the nitrogen atom to which they arebonded, form a heterocycle selected from azetidine, pyrrolidine,piperidine, morpholine, thio-morpholine, perhydroazepine and piperazinewhich is unsubstituted or substituted in the 4-position by a (C₁-C₄)alkyl;

R₂₁ is a hydrogen or a (C₁ -C₇)alkyl;

R₂₂ is a hydrogen or a (C₁ -C₇)alkyl;

R₂₃ and R₂₄ are each independently a hydrogen or a (C₁ -C₇)alkyl;

R₂₅ is a hydrogen or a (C₁ -C₇)alkyl; and

R₂₆ and R₂₇ are each independently a hydrogen or a (C₁ -C₇)alkyl; R₂₇can also be a formyl or a (C₁ -C₇)alkylcarbonyl;

i₂ --or a group Ar₂ --CH═C

in which Ar₂ is as defined above;

i₃ --or a group ##STR5## in which Ar₂ is as defined above; i₄ --or agroup ##STR6## in which Ar₂ is as defined above; i₅ --or a group##STR7## in which: Ar₂ is as defined above;

Am₁ is an amino group substituted by two (C₁ -C₄)alkyls; and

r is two or three;

i₆ --or a group ##STR8## in which: Ar₂ is as defined above;

W₂ is an oxygen atom; a sulfur atom; a sulfinyl; a sulfonyl; or a group--NL₁ --;

L₁ is a hydrogen; a (C₁ -C₄)alkyl; a (C₁ -C₄)alkylcarbonyl; or a group--(CH₂)_(v) -- Am₂ ;

v is one, two or three; and

Am₂ is an amino group which is unsubstituted or monosubstituted ordisubstituted by a (C₁ -C₄)alkyl; Am₂ can also be a pyrrolidino,piperidino or morpholino group;

ii--or a group B₂ of the formula ##STR9## in which J₂ is: ii₁ --either agroup Ar₂ --N

ii₂ --or a group Ar₂ --CH₂ N

ii₃ --or a group ##STR10## ii₄ --or a group ##STR11## ii₅ --or a group##STR12## in which: Ar₂ is as defined above;

r is two or three; and

Am₁ is as defined above;

iii--or a group B₃ of the formula ##STR13## in which J₃ is: a group:##STR14## in which: W₃ is an oxygen atom; a sulfar atom; or a groupNR₃₀, in which R₃₀ is a hydrogen or a (C₁ -C₃)alkyl;

R₂₈ is a hydrogen; a (C₁ -C₆)alkyl; a (C₃ -C₆)alkenyl in which onevinylic carbon atom is not bonded to the nitrogen atom; a2-hydroxyethyl; a (C₃ -C₇)cycloalkyl; a phenyl which is unsubstituted ormonosubstituted or polysubstituted by a substituent selected from ahalogen atom, a trifluoromethyl, a (C₁ -C₄)alkyl, a (C₁ -C₄)alkoxy, anitro, an amino and a hydroxyl, said substituents being identical ordifferent; or a 6-membered heteroaryl containing one or two nitrogenatoms as heteroatoms, said heteroaryl being unsubstituted ormonosubstituted or polysubstituted by a substituent selected from ahalogen atom, a trifluoromethyl, a (C₁ -C₄)alkyl, a (C₁ -C₄)alkoxy, anitro, an amino and a hydroxyl, said substituents being identical ordifferent;

R₂₉ is a hydrogen; a (C₁ -C₆)alkyl which is unsubstituted or substitutedby a hydroxyl and/or by one, two or three fluorine atoms; a (C₃-C₆)cycloalkyl; a (C₁ -C₅)alkoxy (only when W₃ is an oxygen atom); a (C₃-C₆)cycloalkoxy (only when W₃ is an oxygen atom); or a group --NR₃₁ R₃₂containing from zero to seven carbon atoms, R₂₉ being other than anunsubstituted (C₁ -C₄)alkyl when simultaneously W₃ is an oxygen and R₂₈is a phenyl which is unsubstituted or monosubstituted or polysubstitutedby a substituent selected from a halogen atom, a nitro, a hydroxyl, atrifluoromethyl, a (C₁ -C₄)alkyl and a (C₁ -C₄)alkoxy, said substituentsbeing identical or different; a pyridyl; or a pyrimidyl;

or R₂₈ and R₂₉ together form a divalent hydrocarbon group L₂, in whichthe 1-position is bonded to the carbon atom carrying the substituent W₃,the divalent hydrocarbon group L₂ being selected from a trimethylene, acis-propenylene, a tetramethylene, a cis-butenylene, acis,cis-butadienylene, a pentamethylene and a cis-pentenylene, saiddivalent hydrocarbon group L₂ being unsubstituted or substituted by oneor two methyls; and

R₃₁ and R₃₂ are each independently a hydrogen, a (C₁ -C₅)alkyl or a (C₃-C₆)cycloalkyl; or R₃₁ and R₃₂, together with the nitrogen atom to whichthey are bonded, form a heterocycle selected from pyrrolidine,piperidine, morpholine, thiomorpholine (or its S-oxide) and piperazinewhich is unsubstituted or substituted in the 4-position by a (C₁-C₄)alkyl;

iv--or a group B₄ of the formula ##STR15## in which: W₄ is a (C₁-C₈)alkyl or a (C₃ -C₈)cycloalkyl, said alkyl and cycloalkyl groupsbeing unsubstituted or substituted by one or more substituents selectedfrom a halogen atom; a (C₃ -C₆)cycloalkyl; a cyano; a nitro; a hydroxyl;a (C₁ -C₄)alkoxy, a formyloxy; a (C₁ -C₄)alkylcarbonyloxy; anarylcarbonyl; a heteroarylcarbonyl; an oxo; an imino which isunsubstituted or substituted on the nitrogen atom by a (C₁ -C₆)alkyl, a(C₃ -C₆)cycloalkyl, a formyl, a (C₁ -C₄)alkylcarbonyl or anarylcarbonyl; a hydroxyimino which is unsubstituted or substituted onthe oxygen atom by a (C₁ -C₄)alkyl or a phenyl; a group --NR₃₃ R₃₄containing from zero to seven carbon atoms; a group --NR₃₅ R₃₆ ; a group--C(═NR₃₇)NR₃₈ R₃₉, in which the group --NR₃₈ R₃₉ contains from zero toseven carbon atoms; and a group --CON(OR₄₀)R₄₁, said substituents beingidentical or different;

R₃₃ and R₃₄ are each independently a hydrogen, a (C₁ -C₅)alkyl or a (C₃-C₆)cycloalkyl; or R₃₃ and R₃₄, together with the nitrogen atom to whichthey are bonded, form a heterocycle selected from pyrrolidine,piperidine, morpholine, thiomorpholine (or its S-oxide) and piperazinewhich is unsubstituted or substituted in the 4-position by a (C₁-C₄)alkyl;

R₃₅ is a hydrogen or a (C₁ -C₄)alkyl;

R₃₆ is a formyl; a (C₁ -C₄)alkylcarbonyl; an arylcarbonyl; aheteroarylcarbonyl; or a group --C(═W₅)NR₃₈ R₃₉, in which the group--NR₃₈ R₃₉ contains from zero to seven carbon atoms;

W₅ is an oxygen atom; a sulfur atom; a group NR₃₇ ; or a group CHR₄₂ ;

R₃₇ is a hydrogen or a (C₁ -C₄)alkyl; or R₃₇ and R₃₉ together form anethylene group or a trimethylene group;

R₃₈ and R₃₉ are each independently a hydrogen, a (C₁ -C₅)alkyl or a (C₃-C₆)cycloalkyl; or R₃₈ and R₃₉, together with the nitrogen atom to whichthey are bonded, form a heterocycle selected from pyrrolidine,piperidine, morpholine, thiomorpholine (or its S-oxide) and piperazinewhich is unsubstituted or substituted in the 4-position by a (C₁-C₄)alkyl; or R₃₈ is a hydrogen or a (C₁ -C₄)alkyl and R₃₉ and R₃₇together form an ethylene group or a trimethylene group;

R₄₀ and R₄₁ are each independently a (C₁ -C₃)alkyl;

R₄₂ is a cyano; a nitro; or a group SO₂ R₄₃ ;

R₄₃ is a (C₁ -C₄)alkyl or a phenyl; and when W₄ is a cyclic group orwhen a substituent of W₄ is a cyclic group or contains a cyclic group,said cyclic groups can also be substituted on a carbon atom by one ormore (C₁ -C₃)alkyls; and when a substituent of W₄ contains an aryl groupor a heteroaryl group, said aryl or heteroaryl groups can also bemonosubstituted or polysubstituted by a substituent selected from ahalogen atom, a (C₁ -C₄)alkyl, a (C₁ -C₄)alkoxy, a cyano, atrifluoromethyl and a nitro, said substituents being identical ordifferent;

v--or a group B₅ of the formula ##STR16## in which: W₆ and W₇ are each ahydrogen; or W₆ is a hydrogen and W₇ is a hydroxyl;

W₈ is an aryl or a heteroaryl which are unsubstituted or substituted byan aryl, an arylcarbonyl, a heteroaryl or a heteroarylcarbonyl; saidaryl or heteroaryl groups can also be monosubstituted or polysubstitutedon the aromatic or heteroaromatic moiety and on a carbon atom by asubstituent selected from a halogen atom; a cyano; a trifluoromethyl; anitro; a hydroxyl; a (C₁ -C₅)alkoxy; a formyloxy-, a (C₁-C₄)alkylcarbonyloxy; a group --NR₃₃ R₃₄ containing from zero to sevencarbon atoms; a group --NR₃₅ R₃₆ ; a group --C(═NR₃₇)NR₃₈ R₃₉, in whichthe group --NR₃₈ R₃₉ contains from zero to seven carbon atoms; a group--COOR₄₄ ; a group --CONR₄₅ R₄₆, in which the group NR₄₅ R₄₆ containsfrom zero to seven carbon atoms; a mercapto; a group --S(O)_(s) R₄₇ ; a(C₁ -C₅)alkyl; a formyl; and a (C₁ -C₄)alkylcarbonyl, said substituentsbeing identical or different; when W₆ and W₇ are each a hydrogen, W₈ isother than a phenyl which is unsubstituted or monosubstituted orpolysubstituted by a substituent selected from a halogen atom, a nitro,a hydroxyl, a trifluoromethyl and a (C₁ -C₄)alkoxy, said substituentsbeing identical or different; a pyridyl; a thienyl; a pyrimidyl; or animidazolyl which is unsubstituted or substituted by a (C₁ -C₄)alkyl;

or W₇ is a hydrogen and W₆ and W₈, together with a diradical W₉ and thepiperidine carbon atom to which they are bonded, form a spiro ring inwhich W₈ is a phenyl substituted in the ortho position by a diradicalW₉, which is itself joined to W₆, said phenyl being unsubstituted orsubstituted by a substituent selected from a halogen atom, a (C₁-C₃)alkyl, a (C₁ -C₃)alkoxy, a hydroxyl, a (C₁ -C₃)alkylthio, a (C₁-C₃)alkxylsulfinyl and a (C₁ -C₃)alkylsulfonyl; the diradical W₉ is amethylene, a carbonyl or a sulfonyl; and W₆ is an oxygen atom or a group--NR₄₈ --, in which R₄₈ is a hydrogen or a (C₁ -C₃)alkyl;

R₃₃, R₃₄, R₃₅, R₃₆, R₃₇, R₃₈ and R₃₉ are as defined above for the groupB₄ ;

R₄₄ is a hydrogen; a (C₁ -C₅)alkyl; an aryl; a heteroaryl; anarylmethyl; or a heteroarylmethyl;

R₄₅ and R₄₆ are each independently a hydrogen, a (C₁ -C₅)alkyl or a (C₃-C₆)cycloalkyl; or R₄₅ and R₄₆, together with the nitrogen atom to whichthey are bonded, form a heterocycle selected from pyrrolidine,piperidine, morpholine, thiomorpholine (or its S-oxide) and piperazinewhich is unsubstituted or substituted in the 4-position by a (C₁-C₄)alkyl;

s is zero, one or two;

R₄₇ is a (C₁ -C₆)alkyl; a (C₃ -C₆)cycloalkyl; an aryl; or a heteroaryl;and when W₈ or a substituent of W₈ contains a cyclic group, said cyclicgroup can also be substituted by one or more methyls; and when aheteroaryl group forming part of W₈ or of a substituent of W₈ contains anitrogen atom as the heteroatom, said nitrogen atom can also besubstituted by a (C₁ -C₅)alkyl; and when W₈ or a substituent of W₈contains a (C₁ -C₅)alkyl, (C₁ -C₅)alkoxy, formyl or (C₁-C₄)-alkylcarbonyl group, said (C₁ -C₅)alkyl, (C₁ -C₅)alkoxy, formyl or(C₁ -C₄)alkyl-carbonyl groups can also be substituted by a hydroxyl, a(C₁ -C₃)alkoxy or one or more halogen atoms, with the proviso that acarbon atom bonded to a nitrogen atom or to an oxygen atom is notsubstituted by a hydroxyl or an alkoxy group, and with the proviso thata carbon atom in the α-position of a (C₁ -C₄)alkylcarbonyl group is notsubstituted by a chlorine, bromine or iodine atom;

vi--or a group B₆ of the formula ##STR17## in which J₄ is: vi₁ --eithera group ##STR18## in which: W₁₀ is a phenyl which is unsubstituted ormonosubstituted to trisubstituted by a substituent selected from ahalogen atom, a (C₁ -C₆)alkoxy, a (C₁ -C₆)alcyl and a trifluoromethyl,said substituents being identical or different; a benzyl which isunsubstituted or monosubstituted to trisubstituted by a substituentselected from a halogen atom, a (C₁ -C₆)alkoxy, a (C₁ -C₆)alkyl and atrifluoromethyl, said substituents being identical or different; anaphthyl which is unsubstituted or monosubstituted to trisubstituted bya substituent selected from a halogen atom, a (C₁ -C₆)alkoxy, a (C₁-C₆)alkyl and a trifluoromethyl, said substituents being identical ordifferent; a pyridyl which is unsubstituted or monosubstituted ordisubstituted by a substituent selected from a halogen atom, a (C₁-C₆)alkyl and a (C₁ -C₆)alkoxy, said substituents being identical ordifferent; a thienyl; a pyrimidyl; or an imidazolyl; and

W₁₁ is a group --CONHR₄₉ ;

R₄₉ is a group ##STR19## a group ##STR20## a group --CH₂ CH₂ N(CH₃)₂ ;vi₂ --or a group: ##STR21## vi₃ --or a group: ##STR22## vi₄ --or agroup: ##STR23## in which: R₅₀ is a hydrogen, a (C₁ -C₆)alkyl or abenzyl; and

R₅₁ is from one to three substituents selected from a hydrogen, ahalogen atom, a trifluoromethyl, a (C₁ -C₆)alkyl and a (C₁ -C₆)alkoxy,said substituents being identical or different;

vii--or a group B₇ of the formula ##STR24## in which: f and g are eachindependently zero, one, two, three, four or five, with the proviso thatf+g is equal to one, two, three, four or five;

W₁₂ is a direct bond; a (C₁ -C₃)alkylene which is unsubstituted orsubstituted by an oxo, a group OR₅₂, a halogen, a trifluoromethyl or aphenyl which is itself unsubstituted or mono-, di- or tri-substituted bya substituent selected from a hydroxyl, a cyano, a halogen and atrifluoromethyl; a group --S(O)_(k) --; a group (C₁-C₃)alkylene--S(O)_(k) --; a group --S(O)_(k) --(C₁ -C₂)alkylene; agroup --S(O)_(k) --NH--; a group --S(O)_(j) --NR₅₂ --; a group--S(O)_(j) --NR₅₂ --(C₁ -C₂)alkylene; a group --CONR₅₂ --; a group--CONR₅₂ --(C₁ -C₂)alkylene; a group --COO--; or a group --COO--(C₁-C₂)alkylene;

W₁₃ is a group --NR₅₃ --; an oxygen atom; a sulfur atom; a sulfinyl; ora sulfonyl, with the proviso that when W₁₂ is a direct bond and when W₁₄is a (C₁ -C₃)alkylene, W₁₃ is a group --NR₅₃ --;

W₁₄ is a direct bond; a (C₁ -C₃)alkylene which is unsubstituted orsubstituted by an oxo, a group OR₅₂, a halogen, a trifluoromethyl or aphenyl which is itself unsubstituted or mono-, di- or tri-substituted bya substituent selected from a group OR₅₂, a halogen and atrifluoromethyl; a group --S(O)_(k) --; a group (C₁-C₃)alkylene--S(O)_(k) --; a group --S(O)_(k) --(C₁ -C₂)alkylene; agroup --NHS(O)_(j) --; a group --NH--(C₁ -C₂)alkylene--S(O)_(j) --; agroup --S(O)_(j) NR₅ ₂ --; a group --S(O)_(j) --NR₅₂ --(C₁ -C₂)alkylene;a group --NHCO--(C₁ -C₂)alkylene; a group --NR₅₂ --CO--; a group --NR₅₂--(C₁ -C₂)alkylene-CO--; a group --OCO--; or a group (C₁-C₂)alkylene-OCO--;

W₁₅ --W₁₆ together form two adjacent atoms of a cyclic radical of theformula ##STR25## said cyclic radical being a phenyl, a naphthyl or aheteroaryl group selected from a benzimidazolyl, a benzofuranyl, abenzoxazolyl, a furanyl, an imidazolyl, an indolyl, an isoxazolyl, anisothiazolyl, an oxadiazolyl, an oxazolyl, a pyrazinyl, a pyrazolyl, apyridyl, a pyrimidyl, a pyrrolyl, a quinolyl, a tetrazolyl, athiadiazolyl, a thiazolyl, a thienyl and a triazolyl, and said phenyl,naphthyl or heteroaryl cyclic radical being unsubstituted or mono-, di-or tri-substituted by R₅₄ ;

k is zero, one or two;

j is one or two;

R₅₂ is a hydrogen; a (C₁ -C₆)alkyl which is unsubstituted ormonosubstituted or disubstituted by a substituent selected independentlyfrom a hydroxyl, an oxo, a cyano, a halogen atom, a trifluoromethyl anda phenyl which is itself unsubstituted or substituted by a hydroxyl, a(C₁ -C₃)alkyl, a cyano, a halogen, a trifluoromethyl or a (C₁-C₄)alkoxy; a phenyl, a pyridyl or a thiophene, said phenyl, pyridyl orthiophene being unsubstituted or mono-, di- or tri-substituted by asubstituent selected independently from a hydroxyl, a (C₁ -C₄)alkyl, acyano, a halogen atom and a trifluoromethyl; or a (C₁ -C₃)alkoxy;

R₅₃ is a hydrogen; a (C₁ -C₈)alkyl which is unsubstituted ormonosubstituted or polysubstituted by a substituent selected from agroup --OR₅₂, an oxo, a group --NHCOR₅₂, a group --NR₅₅ R₅₆, a cyano, ahalogen atom, a trifluoromethyl and a phenyl which is itselfunsubstituted or substituted by a hydroxyl, a cyano, a halogen atom or atrifluoromethyl; a group --S(O)R₅₇ ; a group --CO₂ R₅₇ ; a group --SO₂R₅₇ ; a group --COR₅₇ ; or a group --CONR₅₆ R₅₇ ;

R₅₄ is a hydrogen; a (C₁ -C₆)alkyl which is unsubstituted ormonosubstituted or disubstituted by a hydrogen or a hydroxyl; an oxo; agroup --OR₅₂ ; a halogen atom; a trifluoromethyl; a nitro; a cyano; agroup --NR₅₅ R₅₆ ; a group --NR₅₅ COR₅₆ ; a group --NR₅₅ CO₂ R₅₆ ; agroup --NHS(O)_(j) R₅₂ ; a group --NR₅₅ S(O)_(j) R₅₆ ; a group --CONR₅₅R₅₆ ; a group --COR₅₂ ; a group --CO₂ R₅₂ ; a group --S(O)_(j) R₅₂ ; ora heteroaryl group, said heteroaryl being selected from abenzimidazolyl, a benzofuranyl, a benzoxazolyl, a furanyl, animidazolyl, an indolyl, an isoxazolyl, an isothiazolyl, an oxadiazolyl,an oxazolyl, a pyrazinyl, a pyrazolyl, a pyridyl, a pyrimidinyl, apyrrolyl, a quinolyl, a tetrazolyl, a thiadiazolyl,. a thiazolyl, athienyl and a triazolyl, and said heteroaryl being unsubstituted ormonosubstituted or disubstituted by R₅₈ ;

R₅₅ is R₅₂ ;

R₅₆ is R₅₂ ;

or R₅₅ and R₅₆, together with the atoms to which they are bonded, form afive-, six- or seven-membered, saturated monocyclic heterocyclecontaining one or two heteroatoms, said heteroatoms being selectedindependently from a nitrogen atom, an oxygen atom and a sulfur atom,said heterocycle being unsubstituted or monosubstituted or disubstitutedby a substituent selected from a hydroxyl, an oxo, a cyano, a halogenatom and a trifluoromethyl;

R₅₇ is a (C₁ -C₆)alkyl which is unsubstituted or mono-, di- ortri-substituted by a substituent selected from a hydroxyl, an oxo, acyano, a group --OR₅₂, a group --NR₅₅ R₅₆, a group --NR₅₅ COR₅₆, ahalogen atom, a trifluoromethyl and a phenyl which is itselfunsubstituted or mono-, di- or tri-substituted by a substituent selectedfrom a hydroxyl, an oxo, a cyano, a group --NHR₅₂, a group --NR₅₅ R₅₆, agroup --NR₅₅ COR₅₆, a halogen atom, a trifluoromethyl and a (C₁-C₃)alkyl;

R₅₈ is a hydrogen; a (C₁ -C₆)alkyl which is unsubstituted ormonosubstituted or disubstituted by a hydrogen or a hydroxyl; an oxo; agroup --OR₅₂ ; a trifluoromethyl; a nitro; a cyano; a group --NR₅₅ R₅₆ ;a group --NR₅₅ COR₅₆ ; a group --NR₅₅ CO₂ R₅₆ ; a group --NHS(O)_(j) R₅₂; a group --NR₅₅ S(O)_(j) R₅₆ ; a group --CONR₅₅ R₅₆ ; a group --COR₅₂ ;a group --CO₂ R₅₂ ; a group --S(O)_(j) R₅₂ ; or a phenyl, and the groupB₇ being other than the group B₅ when W₇ is a hydrogen and W₆ and W₈,together with a diradical W₉ and the piperidine carbon atom to whichthey are bonded, form a spiro ring;

viii--or a group B₈ of the formula ##STR26## in which: W₁₇ is a directbond; a double bond; or a divalent hydrocarbon radical;

W₁₈ is a radical which is joined to the carbon atom of the heterocycleeither by a single bond when W₁₇ is a double bond, or by a double bondin the other cases;

W₁₉ is an unsubstituted or optionally substituted heteroatom;

W₂₀ is a hydrocarbon radical of which the 1-position is joined to W₁₉ ;and

the meanings of W₁₇, W₁₈, W₁₉ and W₂₀ are selected from:

(a) W₁₇ is a direct bond; W₁₈ is an oxo or thioxo group; W₁₉ is an oxyor thio group or a group NR₅₉ ; and W₂₀ is a hydrocarbon radical L₃ ; or

(b) W₁₇ is a direct bond; W₁₈ is a group NR₆₀ ; W₁₉ is a group NR₆₁ ;and W₂₀ is a hydrocarbon radical L₃ ; or

(c) W₁₇ is a double bond; W₁₈ is a group OR₆₁, SR₆₁ or NR₆₂ R₆₃ ; W₁₉ isa nitrogen atom; and W₂₀ is a hydrocarbon radical L₃ ; or

(d) W₁₇ is a methylene which is unsubstituted or substituted by one ortwo methyl groups; W₁₈ is an oxo or thioxo group or a group NR₆₄ ; W₁₉is an oxy, thio, sulfinyl or sulfonyl group or a group NR₁₉ ; and W₂₀ isa hydrocarbon radical L₄ ; or

(e) W₁₇ is a direct bond; W₁₉ is an oxo or thioxo group or a group NR₆₄; W₁₉ is a nitrogen atom; and W₂₀ is a hydrocarbon radical L₅ ; or

(f) W₁₇ is a methine group which is unsubstituted or substituted by oneor two methyl groups; W₁₈ is an oxo or thioxo group or a group NR₆₄ ;W₁₉ is a nitrogen atom; and W₂₀ is a hydrocarbon radical L₆ ; and

(g) W₁₇ is a cis-vinylene group which is unsubstituted or substituted byone or two methyl groups; W₁₈ is an oxo or thioxo group or a group NR₆₄; W₁₉ is a nitrogen atom; and W₂₀ is a hydrocarbon radical L₇ ;

R₅₉ is a hydrogen; a (C₁ -C₃)alkyl; a group --CH₂ COOR₆ ₅ ; or a group--CH₂ CON₆₆ R₆₇ ;

R₆₉ is a hydrogen; a (C₁ -C₃)alkyl; a cyano; a nitro; or a (C₁-C₃)alkylsulfonyl group;

R₆₁ is a hydrogen or a (C₁ -C₃)alkyl;

R₆₂ and R₆₃ are each independently a hydrogen or a (C₁ -C₃)alkyl;

or R₆₂ and R₆₃, together with the nitrogen atom to which they arebonded, form a heterocycle selected from pyrrolidine, piperidine,morpholine, thiomorpholine (or its S-oxide) and piperazine which isunsubstituted or substituted in the 4-position by a (C₁ -C₄)alkyl;

R₆₄ is a hydrogen or a (C₁ -C₃)alkyl;

R₆₅ is a hydrogen or a (C₁ -C₃)alkyl;

R₆₆ and R₆₇ are each independently a hydrogen; a (C₁ -C₃)alkyl; aphenyl; or a benzyl;

L₃ is an ethylene, a cis-vinylene, a trimethylene or a tetramethylene,said hydrocarbon radical L₃ being unsubstituted or substituted by one ortwo methyl groups;

L₄ is an ethylene or a trimethylene, said hydrocarbon radical L₄ beingunsubstituted or substituted by one or two methyl groups;

L₅ is a prop-2-en-1-yliden-3-yl which is unsubstituted or substituted byone or two methyl groups;

L₆ is a cis-vinylene which is unsubstituted or substituted by one or twomethyl groups; and

L₇ is a methine which is unsubstituted or substituted by a (C₁-C₃)alkyl;

ix--or a group B₉ of the formula ##STR27## in which J₅ is: a group##STR28## in which: X₂ is a (C₁ -C₆)alkyl; a group --CH₂ --OR₆₈ ; agroup --CH₂ --SR₆₈ ; a group --CH₂ --S(O)R₆₉ ; a group --CH₂ --SO₂ R₆₉ ;a group --COOR₆₈ ; a group --C(═W₂₄)NR₇₀ R₇₁ ; a group--C(R₆₈)(OR₇₂)(OR₇₃); a group --CH₂ NR₆₈ C(═W₂₄)R₇₄ ; a group --CH₂--NR₆₈ COOR₇₄ ; or a group --CH₂ NR₆₈ C(═W₂₄)NR₇₀ R₇₁ ;

W₂₁ is a direct bond and W₂₂ is a hydrocarbon radical of which the1-position is joined to W₂₁, the hydrocarbon radical W₂₂ being selectedfrom a trimethylene, a tetramethylene, a cis-1-butenylene and acis,cis-butadienylene;

or W₂₁ is a group NR₇₅ and W₂₂ is a hydrocarbon radical selected from anethylene, a trimethylene and a cis-vinylene;

or W₂₁ is a nitrogen atom and W₂₂ is a cis,cis-prop-2-en-1-yliden-3-ylradical of which the 1-position is joined to W₂₁ ;

W₂₃ is an oxygen atom or a sulfur atom;

W₂₄ is an oxygen atom or a sulfur atom;

R₆₈ is a hydrogen or a (C₁ -C₆)alkyl;

R₆₉ is a (C₁ -C₆)alkyl;

R₇₀ and R₇₁ are each independently a hydrogen; a (C₁ -C₆)alkyl which isunsubstituted or substituted by a hydroxyl or a (C₁ -C₃)alkoxy; anωHO-(C₁ -C₆)alkyl; an ω(C₁ -C₃)alkoxy-(C₁ -C₆)alkyl; an ω-phenyl-(C₁-C₆)alkyl; an ω-R₇₆ OOC-(C₁ -C₆)alkyl; or an ω-R₇₇ R₇₈ NCO-(C₁-C₆)alkyl;

or R₇₀ and R₇₁, together with the nitrogen atom to which they arebonded, form a heterocycle selected from pyrrolidine, piperidine,morpholine, thiomorpholine (or its S-oxide) and piperazine which isunsubstituted or substituted in the 4-position by a methyl group or anethyl group;

R₇₂ and R₇₃ are each independently a (C₁ -C₃)alkyl;

or R₇₂ and R₇₃ together form a divalent hydrocarbon radical selectedfrom an ethylene and a trimethylene;

R₇₄ is a hydrogen or a (C₁ -C₆)alkyl;

R₇₅ is a hydrogen or a (C₁ -C₆)alkyl;

R₇₆ is a hydrogen or a (C₁ -C₃)alkyl; and

R₇₇ and R₇₈ are each independently a hydrogen or a (C₁ -C₃)alkyl;

x--or a group B₁₀ of the formula ##STR29## in which J₆ is: a group##STR30## in which: X₁ is as defined above for the group B₁, X₁ beingother than hydrogen when W₂₅ is a (C₁ -C₇)alkyl or a (C₃ -C₇)cycloalkyl;

W₂₅ is a (C₁ -C₇)alkyl or a (C₃ -C₇)cycloalkyl; W₂₅ can also be a group--NR₇₉ R₈₀ when X₁ is a hydrogen, a cyano, a carboxyl, a (C₁-C₇)alkoxycarbonyl or a group --CONR₁₉ R₂₀ ; and

R₇₉ and R₈₀ are each independently a (C₁ -C₇)alkyl;

or R₇₉ and R₈₀, together with the nitrogen atom to which they arebonded, form a heterocycle selected from azetidine, pyrrolidine,piperidine, morpholine, thio-morpholine and perhydroazepine,

with the proviso that:

1/when simultaneously:

R₂ is a methyl group or R₁ and R₂ together form a group --(CH₂)₃ --;

Ar₁ is a 3,4-dichlorophenyl;

T is a group --CH₂ --; a group --CO--; a group --COO--; or a group--CONR₃ ;

A is a direct bond; a group --(CH₂)_(t) -- in which t is one, two orthree; or a vinylene group;

or --T--A-- is the group --SO₂ --; and

Z is a phenyl which is unsubstituted or monosubstituted orpolysubstituted by a halogen, a (C₁ -C₄)alkyl, a (C₁ -C₄)alkoxy or anitro,

B is a group B₁ of the formula ##STR31## in which J₁ is a group##STR32## in which: x is zero;

Ar₂ is a pyrid-2-yl or a phenyl which is unsubstituted or substituted bya halogen, a methyl or a (C₁ -C₄)alkoxy; and

X₁ is other than a group selected from:

formyl;

(C₁ -C₆)alkylcarbonyl;

--(CH₂)_(m) --OR₄ in which m is zero or one and R₄ is a hydrogen or a(C₁ -C₇)alkyl;

--(CH₂)_(m) --OCOR₅ in which m is zero or one and R₅ is a hydrogen or a(C₁ -C₆)alkyl;

--(CH₂)_(m) --OCONH(C₁ -C₇)alkyl in which m is one;

--NR₈ R₉ in which R₈ and R₉ are each independently a hydrogen or a (C₁-C₇)alkyl;

R₉ can also be a (C₃ -C₇)cycloalkylmethyl, a benzyl or a phenyl; or R₈and R₉, together with the nitrogen atom to which they are bonded, form aheterocycle selected from azetidine, pyrrolidine, piperidine,morpholine, thiomorpholine and perhydroazepine;

--(CH₂)_(p) --NR₁₀ R₁₁ in which p is one and R₁₀ and R₁₁ are eachindependently a hydrogen or a (C₁ -C₇)alkyl; R₁₁ can also be a (C₃-C₇)cycloalkylmethyl or a benzyl;

--NR₁₂ COR₁₃ in which R₁₂ is a hydrogen or a (C₁ -C₄)alkyl and R₁₃ is ahydrogen, a (C₁ -C₇)alkyl, a phenyl, a benzyl, a pyridyl or a (C₃-C₇)cycloalkyl which is unsubstituted or substituted by one or moremethyls; or R₁₂ and R₁₃ together are a group --(CH₂)_(u) -- in which uis three or four;

--(CH₂)_(p) --NR₁₄ C(═W₁)R₁₆ in which p is one, W₁ is an oxygen atom,R₁₄ is a hydrogen or a (C₁ -C₄)alkyl and R₁₆ is a hydrogen, a (C₁-C₇)alkyl, a phenyl, a benzyl, a pyridyl or a (C₃ -C₇)cycloalkyl whichis unsubstituted or substituted by one or more methyls;

--(CH₂)_(m) --NR₁₄ COOR₁₇ in which m is zero or one, R₁₄ is a hydrogenor a (C₁ -C₄)alkyl and R₁₇ is a (C₁ -C₇)alkyl or a phenyl;

--(CH₂)_(m) --NR₁₄ SO₂ R₁₈ in which m is zero or one, R₁₄ is a hydrogenor a (C₁ -C₄)alkyl and R₁₈ is a (C₁ -C₇)alkyl, an amino which is free orsubstituted by one or two (C₁ -C₇)alkyls, or a phenyl which isunsubstituted or monosubstituted or polysubstituted by a substituentselected from a halogen atom, a (C₁ -C₇)alkyl, a trifluoromethyl, ahydroxyl, a (C₁ -C₇)alkoxy, a carboxyl, a (C₁ -C₇)alkoxycarbonyl, a (C₁-C₇)alkylcarbonyloxy, a cyano, a nitro and an amino which is free orsubstituted by one or two (C₁ -C₇)alkyls, said substituents beingidentical or different;

--(CH₂)_(m) --NR₁₄ C(═W₁)NR₁₉ R₂₀ in which m is zero or one, W₁ is anoxygen atom, R₁₄ is a hydrogen or a (C₁ -C₄)alkyl and R₁₉ and R₂₀ areeach independently a hydrogen or a (C₁ -C₇)alkyl; R₂₀ can also be a (C₃-C₇)cycloalkyl, a (C₃ -C₇)cycloalkylmethyl, a hydroxyl, a (C₁-C₄)alkoxy, a benzyl or a phenyl; or R₁₉ and R₂₀, together with thenitrogen atom to which they are bonded, form a heterocycle selected fromazetidine, pyrrolidine, piperidine, morpholine, thiomorpholine andperhydroazepine;

--(CH₂)_(n) --COOR₂₁ in which n is zero and R₂₁ is a (C₁ -C₇)alkyl;

--(CH₂)_(n) --C(═W₁)NR₁₉ R₂₀ in which n is zero, W₁ is an oxygen atomand R₁₉ and R₂₀ are as defined above; and

--CN;

or X₁ does not form a double bond between the carbon atom to which it isbonded and the adjacent carbon atom of the piperidine ring;

or Ar₂ and X₁, together with the carbon atom to which they are bonded,are other than a group of the formula ##STR33## 2/ when R₁ is hydrogen,R₂ is the methyl group, Ar₁ is the 3,4-dichlorophenyl group and T--A--Zis the thenoyl group, B is the group B₁ in which J₁ is the group##STR34## in which x is one, Ar₂ is the phenyl group and X₁ is otherthan hydrogen;

3/ when R₁ is hydrogen, R₂ is the methyl group, Ar₁ is the3,4-dichlorophenyl group and T--A--Z is the 2,4-dichlorobenzoyl group, Bis the group B₁ in which J₁ is the group ##STR35## in which x is one,Ar₂ is the phenyl group and X₁ is other than hydrogen; or

4/ when R₁ and R₂ together form a group --(CH₂)₃ --, Ar₁ is the3,4-dichlorophenyl group and T--A--Z is the 2-(3-methoxyphenyl)acetylgroup, B is the group B₁ in which J₁ is the group ##STR36## in which xis one, Ar₂ is phenyl and X₁ is other than hydrogen; and their salts,where appropriate, with mineral or organic acids.

The compounds of formula (I) according to the invention include theoptically pure isomers as well as the racemates.

It is possible to form salts of the compounds of formula (I). Thesesalts include those with mineral or organic acids which permit asuitable separation or crystallization of the compounds of formula (I),such as picric acid, oxalic acid or an optically active acid, forexample a mandelic or camphosulfonic acid, as well as those with mineralor organic acids which form pharmaceutically acceptable salts such asthe hydrochloride, hydrobromide, sulfate, hydrogensulfate,dihydrogenphosphate, methanesulfonate, methylsulfate, maleate, fumarate,naphthalene-2-sulfonate, glycolate, gluconate, citrate, isethionate,benzenesulfonate and para-toluenesulfonate.

More particularly, the radical Z can be a phenyl group, which can beunsubstituted or may contain one or more substituents.

When Z is a phenyl group, it can be monosubstituted or disubstituted,especially in the 2,4-position but also, for example, in the 2,3-, 4,5-,3,4- or 3,5-position; it can also be trisubstituted, especially in the2,4,6-position but also, for example, in the 2,3,4-, 2,3,5-, 2,4,5- or3,4,5-position, tetrasubstituted, for example in the 2,3,4,5-position,or pentasubstituted.

The radical Z can also be a bicyclic aromatic group such as 1- or2-naphthyl or 1-, 2-, 3-, 4-, 5-, 6- or 7-indenyl, in which one or morebonds can be hydrogenated, it being possible for said groups to beunsubstituted or optionally to contain one or more substituents such asalkyl, phenyl, cyano, hydroxyalkyl, hydroxyl, oxo, alkylcarbonylamino,alkoxycarbonyl, thioalkyl, halogen, alkoxy and trifluoromethyl groups,in which the alkyls are C₁ -C₄.

The radical Z can also be a group Z.sup.• selected from pyridyl,thiadiazolyl, indolyl, indazolyl, imidazolyl, benzimidazolyl,benzotriazolyl, benzofuranyl, benzothienyl, benzothiazolyl,benzisothiazolyl, quinolyl, isoquinolyl, benzoxazolyl, benzisoxazolyl,benzoxazinyl, benzodioxinyl, isoxazolyl, benzopyranyl, thiazolyl,thienyl, furyl, pyranyl, chromenyl, isobenzofiranyl, pyrrolyl,pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl,phthalazinyl, quinazolinyl, acridinyl, isothiazolyl, isochromanyl andchromanyl, in which one or more double bonds can be hydrogenated, itbeing possible for said groups to be unsubstituted or optionally tocontain one or more substituents such as alkyl, phenyl, cyano,hydroxyalkyl, hydroxyl, alkylcarbonylamino, alkoxycarbonyl and thioalkylgroups, in which the alkyl and alkoxy groups are C₁ -C₄.

In the present description the alkyl or alkoxy groups are linear orbranched; halogen atom is understood as meaning a chlorine, bromine,fluorine or iodine atom.

In the present description, when B is a group B₄ or B₅, aryl isunderstood as meaning a phenyl radical or a C₉ -C₁₀ ortho-fused bicycliccarbocyclic radical in which at least one of the rings is aromatic;heteroaryl is understood as meaning either a five- or six-memberedmonocyclic aromatic heterocycle containing from one to four heteroatoms,said heteroatoms being selected from an oxygen atom, a sulfur atom and anitrogen atom, and said heterocycle being bonded by a carbon atom of thering, or an eight- to ten-membered ortho-fused bicyclic aromaticheterocycle containing from one to four heteroatoms as defined above.

In the substituents of the group Z=phenyl, (C₁ -C₁₀)alkyl is understoodas meaning for example a methyl, an ethyl, an n-propyl, an isopropyl, ann-butyl, an isobutyl, a sec-butyl, a tert-butyl, a pentyl or n-pentyl, ahexyl or n-hexyl, a heptyl or n-heptyl, an octyl or n-octyl, a nonyl orn-nonyl or a decyl or n-decyl; (C₃ -C₈)-cycloalkyl optionallysubstituted by a methyl is understood as meaning for example acyclopropyl, a cyclobutyl, a cyclopentyl, a 1-, 2- or3-methylcyclopentyl, a cyclohexyl, a 1-, 2-, 3- or 4-methylcyclohexyl, acycloheptyl or a cyclooctyl; (C₁ -C₁₀)alkoxy is understood as meaningfor example a methoxy, an ethoxy, an n-propoxy, an isopropoxy, ann-butoxy, an isobutoxy, a sec-butoxy, a tert-butoxy, a pentoxy, ahexyloxy, a heptyloxy, an octyloxy, a nonyloxy or a decyloxy; (C₃-C₈)cycloalkoxy optionally substituted by a methyl is understood asmeaning for example a cyclopropoxy, a cyclobutoxy, a cyclopentoxy, a 1-,2- or 3-methylcyclopentoxy, a cyclohexyloxy, a 1-, 2-, 3- or4-methylcyclohexyloxy, a cycloheptyloxy or a cyclooctyloxy; (C₁-C₁₀)alkylthio is understood as meaning for example a methylthio, anethylthio, an n-propylthio, an isopropylthio, an n-butylthio, anisobutylthio, a sec-butylthio, a tert-butylthio, a pentylthio, ahexylthio, a heptylthio, an octylthio, a nonylthio or a decylthio; (C₁-C₆)alkylcarbonyloxy is understood as meaning for example an acetoxy, apropionyloxy, a butyryloxy, a valeryloxy, a caproyloxy or aheptanoyloxy; (C₁ -C₆)alkylcarbonylamino is understood as meaning forexample an acetylamino, a propionylamino, a butyrylamino, anisobutyrylamino, a valerylamino, a caproylamino or an heptanoylamino;(C₁ -C₄)alkoxycarbonyl is understood as meaning for example amethoxycarbonyl, an ethoxycarbonyl, an n-propoxycarbonyl, anisopropoxycarbonyl, an n-butoxycarbonyl, an isobutoxycarbonyl, asec-butoxycarbonyl or a tert-butoxycarbonyl; and (C₃-C₇)cycloalkoxycarbonyl is understood as meaning for example acyclopropoxycarbonyl, a cyclobutoxycarbonyl, a cyclopentoxycarbonyl, acyclohexyloxycarbonyl or a cycloheptyloxycarbonyl.

The invention relates particularly to compounds of formula (I) in which:

Z is Z as defined above;

R₁ and R₂ together form a group --(CH₂)₃ --;

Ar₁ is a 3,4-dichlorophenyl;

T is a group --CO--;

A is a direct bond; and

B is as defined for a compound of formula (I),

and their salts, where appropriate, with mineral or organic acids.

Among these compounds, those of the formula ##STR37## in which: Z.sup.•is as defined above; and

B.sup.• is a group of the formula ##STR38## in which J.sup.• is: i.sup.•--either a group of the structure ##STR39## in which: W.sup.• is aphenyl or a benzyl and R₁₉ and R₂₀ are as defined for a compound offormula (I);

or W.sup.• is a group --NR₇₉ R₈₀ in which R₇₉ and R₈₀ are as defined for(I) and R₁₉ and R₂₀ are each hydrogen;

i--or a group of the structure ##STR40## in which: R.sup.• is hydrogen,a methyl group, an acetyl group, a methoxycarbonyl group, adimethylaminocarbonyl group or a methanesulfonyl group,

and their salts, especially pharmaceutically acceptable salts, areadvantageous.

Among these compounds, those of the formula ##STR41## in which: B.sup.•is as defined for a compound of formula (I); and

Z.sup.•• is a pyridyl, for example a 4-pyridyl, a 2-thienyl, a3-thienyl, a 2-furyl or a 3-furyl,

and their salts, especially pharmaceutically acceptable salts, areparticularly advantageous.

Among these compounds, those of the formula ##STR42## in which: Z.sup.••is as defined for a compound of formula (I.sup.••),

and their salts, especially pharmaceutically acceptable salts, are ofvery great interest.

Advantageously the radical Z is a phenyl which is unsubstituted ormonosubstituted or polysubstituted by a halogen atom, more particularlya chlorine, fluorine or iodine atom, a trifluoromethyl, a (C₁ -C₄)alkyl,a hydroxyl or a (C₁ -C₄)alkoxy; a naphthyl which is unsubstituted ormonosubstituted or polysubstituted by a halogen, a trifluoromethyl, a(C₁ -C₄)alkyl, a hydroxyl or a (C₁ -C₄)alkoxy; a pyridyl; a thienyl; anindolyl; a quinolyl; a benzothienyl; or an imidazolyl.

The invention relates particularly to compounds of formula (I) in which:

Z is Z' and is:

a phenyl which is unsubstituted or monosubstituted or polysubstituted bya substituent selected from a halogen atom; a trifluoromethyl; a cyano;a hydroxyl; a nitro; an amino which is unsubstituted or monosubstitutedor disubstituted by a (C₁ -C₄)alkyl; a benzylamino; a carboxyl; a (C₁-C₁₀)alkyl; a (C₃ -C₈)cycloalkyl which is unsubstituted ormonosubstituted or polysubstituted by a methyl; a (C₁ -C₁₀)alkoxy; a (C₃-C₈)cycloalkoxy which is unsubstituted or monosubstituted orpolysubstituted by a methyl; a mercapto; a (C₁ -C₁₀)alkylthio; aformyloxy; a (₁ -C₆)alkylcarbonyloxy; a formylamino; a (C₁-C₆)alkylcarbonylamino; a benzoylamino; a (C₁ -C₄)alkoxycarbonyl; a (C₃-C₇)cycloalkoxycarbonyl; a carbamoyl which is unsubstituted ormonosubstituted or disubstituted by a (C₁ -C₄)alkyl; a ureido which isunsubstituted or monosubstituted or disubstituted in the 3-position by a(C₁ -C₄)alkyl or a (C₃ -C₇)cycloalkyl; and a(pyrrolidin-1-yl)-carbonylamino, said substituents being identical ordifferent;

a naphthyl which is unsubstituted or monosubstituted or polysubstitutedby a halogen, a trifluoromethyl, a (C₁ -C₄)alkyl, a hydroxyl or a (C₁-C₄)alkoxy; or

a pyridyl; a thienyl; an indolyl; a quinolyl; a benzothienyl; or animidazolyl, and their salts with mineral or organic acids.

The substituent Ar₁ is preferably a phenyl group which is advantageouslysubstituted by two chlorine atoms, more particularly in the 3- and4-positions.

According to the present invention, the preferred compounds are those inwhich simultaneously:

Z is Z';

Ar₁ is a 3,4-dichlorophenyl;

R₁ and R₂ together form a group --(CH₂)₃ or --(CH₂)₄ --; and

B, T and A are as defined for a compound of formula (I),

and their salts, especially pharmaceutically acceptable salts.

When B is a group B₃, W₃ is advantageously an oxygen or sulfur atom, R₂₈is hydrogen, a (C₁ -C₆)alkyl, a (C₃ -C₇)cycloalkyl, preferablycyclohexyl, or a (C₃ -C₄)alk-2-en-1-yl, preferably alkyl, and R₂₉ ishydrogen, a (C₁ -C₆)alkyl, a trifluoromethyl or a (C₁ -C₄)alkylamino,preferably methylamino, or, only when R₂₈ is other than hydrogen, R₂₉ isa di(C₁ -C₅)alkylamino, preferably dimethylamino, or R₂₈ and R₂₉together are a 1,3-propylene, 1,4-butylene or cis,cis-1,4-butadienylenegroup. Consequently the compounds of formula (I) in which B is B₃ andW₃, R₂₈ and R₂₉ are as just defined, and their salts, especiallypharmaceutically acceptable salts, are advantageous products.

The compounds of this subclass of formula (I) in which simultaneously:

B is a group B₃ in which:

either W₃ is oxygen, R₂₉ is a (C₁ -C₄)alkyl or a trifluoromethyl and R₂₈is a (C₁ -C₆)alkyl, especially an ethyl;

or W₃ is oxygen, R₂₈ is an alkyl or a cyclohexyl and R₂₉ is a methyl;

or W₃ is oxygen, R₂₈ is an ethyl and R₂₉ is a methylamino or adimethylamino;

or W₃ is oxygen and R₂₈ and R₂₉ together form a 1,3-propylene,1,4-butylene or cis,cis-1,4-butadienyl group;

or W₃ is sulfur and R₂₈ and R₂₉ together form a 1,4-butylene group;

R₁ and R₂ together form a group --(CH₂)₃ -- or --(CH₂)₄ --;

Ar₁ is a 3,4-dichlorophenyl;

Z=Z'; and

T and A are as defined above for a compound of formula (I),

and their salts, especially pharmaceutically acceptable salts, areparticularly preferred.

When B is a group B₄, W₄ is advantageously a (C₁ -C₈)alkyl groupsubstituted by a hydroxyl, oxo, hydroxyimino, (C₁ -C₄)alkoxyimino, (C₁-C₄)alkanoyloxy, (C₁ -C₄)alkanoylamino or (C₁ -C₄)alkoxy group or at thesame time by an oxo group and a hydroxyl or (C₁ -C₄)alkoxy group or agroup --NR₃₃ R₃₄. Consequently the compounds of formula (I) in which Bis a group B₄ and W₄ is an alkyl group substituted by a hydroxyl, oxo,hydroxyimino, (C₁ -C₄)alkoxyimino, (C₁ -C₄)alkanoyloxy, (C₁-C₄)alkanoylamino or (C₁ -C₄)alkoxy group or at the same time by an oxogroup and a hydroxyl or (C₁ -C₄)alkoxy group or a group --NR₃₃ R₃₄, andtheir salts, especially pharmaceutically acceptable salts, areadvantageous products.

The compounds of this subclass of formula (I) in which simultaneously:

B is B₄ in which: W₄ is 1-hydroxypropyl, 1-hydroxyethyl, 1-hydroxybutyl,2-hydroxybut-2-yl, 4-hydroxyhept-4-yl, 2-hydroxyethyl,1-hydroxyiminopropyl (syn or anti), 1-methoxyiminopropyl (syn or anti),2-acetoxyethyl, 2-acetamidoethyl, carboxyl, ethoxycarbonyl orpyrrolidin-1-ylcarbonyl;

R₁ and R₂ together form a group --(CH₂)₃ -- or --(CH₂)₄ --;

Ar₁ is a 3,4-dichlorophenyl;

Z=Z'; and

T and A are as defined above for a compound of formula (I),

and their salts, especially pharmaceutically acceptable salts, areparticularly preferred.

When B is a group B₅, W₆ is advantageously a hydrogen, W₇ is a hydroxyland W₈ is a phenyl which is unsubstituted or substituted by a methoxy, ahydroxyl, a methylthio or a methylsulfinyl; or W₆ and W₇ are hydrogenand W₈ is a pyridyl, pyrimidyl or thienyl group substituted by ahalogen, especially chlorine or fluorine, or by one of the followinggroups: cyano, trifluoromethyl, hydroxyl, (C₁ -C₅)alkoxy, especiallymethoxy or ethoxy, formyloxy, (C₁ -C₄)alkylcarbonyloxy, especiallyacetoxy, amino, methylamino, dimethylamino, acetamido, imidazolin-2-yl,carboxyl, methoxycarbonyl, benzyloxycarbonyl, ethoxycarbonyl, carbamoyl,N,N-dimethylcarbamoyl, pyrrolidinocarbonyl, N-methylcarbamoyl,methylthio, methylsulfinyl, methylsulfonyl, (C₁ -C₄)alkyl, especiallymethyl, ethyl, propyl, butyl, isopropyl, 2-methylpropyl or tert-butyl,formyl or (C₁ -C₄)alkylcarbonyl, especially acetyl or propionyl; anindenyl, naphthyl, furyl, pyrrolyl, 1,3,4-oxadiazol-2-yl orbenz[d]isoxazol-3-yl group which is unsubstituted or substituted by oneof the substituents mentioned above for the pyridyl, pyrimidyl orthienyl groups; an imidazol-2-yl substituted by one of the substituentsmentioned above for the pyridyl, pyrimidyl or thienyl groups, except fora (C₁ -C₄)alkyl; or a phenyl group substituted by one of thesubstituents mentioned above for the pyridyl, pyrimidyl or thienylgroups, except for halogens and hydroxyl, trifluoromethyl, (C₁ -C₄)alkyland (C₁ -C₄)alkoxy groups; or W₇ is hydrogen and W₆ and W₈, togetherwith a diradical W₉ and the piperidine carbon atom to which they arebonded, form a spiro ring in which W₈ is a phenyl substituted in theortho position by the diradical W₉, which is itselfjoined to W₆, saidphenyl being unsubstituted or substituted by a methoxy, a hydroxyl, amethylthio or a methylsulfinyl; the diradical W₉ is a methylene or acarbonyl; and W₆ is an oxy group. Consequently the compounds of formula(I) in which B is B₅ and W₆, W₇ and W₈ are as just defined, and theirsalts, especially pharmaceutically acceptable salts, are advantageousproducts.

The compounds of this subclass of formula (I) in which simultaneously:

B is a group B₅ in which: W₇ is a hydroxyl, W₆ is a hydrogen and W₈ is aphenyl; or W₆ and W₇ are hydrogen and W₈ is selected from the follovinggroups: 5-methyl-1,3,4-oxadiazol-2-yl, 4-ethoxycarbonylimidazol-2-yl,2-fluoropyrid-3-yl, 2-methylthiophenyl, 4-methylthiophenyl,2-methylsulfinylphenyl, 4-methylsulfinylphenyl and4-(N-methylcarbamoyl)phenyl; or W₇ is hydrogen and W₆ and W₈, togetherwith the piperidine to which they are bonded, form aspiro[isobenzofuran-1(3H),4'-piperid]-1-yl group or a3-oxospiro[isobenzofuran-1(3h),4'-piperid]-1'-yl group;

R₁ and R₂ together form a group --(CH₂)₃ -- or --(CH₂)₄ --;

Ar₁ is a 3,4-dichlorophenyl;

Z=Z'; and

T and A are as defined above for a compound of formula (I),

and their salts, especially pharmaceutically acceptable salts, areparticularly preferred.

Another group of preferred compounds of the invention consists of thecompounds of formula (I) in which R₁, R₂, Ar₁, T, A and Z are as definedabove for (I) and B is the group B₆.

The particularly preferred compounds of formula (I) are those in whichsimultaneously:

B is a group B₆ ;

R₁ and R₂ together form a group --(CH₂)₃ -- or --(CH₂)₄ --;

Ar₁ is a 3,4-dichlorophenyl;

Z=Z'; and

T and A are as defined above for a compound of formula (I),

and their salts, especially pharmaceutically acceptable salts.

When B is a group B₇, f is advantageously one and g is two, or f is oneand g is one and W₁₂, W₁₃, W₁₄, W₁₅ and W₁₆, together with the carbonatom to which they are bonded, form one of the structures 1 to 201described below, optionally substituted by a halogen, a (C₁ -C₇)alkyl ora (C₁ -C₇)alkoxy: ##STR43##

Consequently the compounds of formula (I) in which B is B₇ and g, f,W₁₂, W₁₃, W₁₄, W₁₅ and W₁₆ are as just defined, and their salts,especially pharmaceutically acceptable salts, are advantageous products.

The compounds of this subclass of formula (I) in which simultaneously:

B is a group B₇ selected from:

a) a 1-methanesulfonylspiro(indoline-3,4'-piperid-1'-yl)

b) a 1-benzyloxycarbonylspiro(indoline-3,4'-piperid-1'-yl)

c) a spiro(indoline-3,4'-piperid-1'-yl)

d) a 1-acetylspiro(indoline-3,4'-piperid-1'-yl)

e) a 1-propionylspiro(indoline-3,4'-piperid-1'-yl)

f) a 1-formylspiro(indoline-3,4'-piperid-1'-yl)

g) a 1-tert-butylcarbonylspiro(indoline-3,4'-piperid-1'-yl)

h) a 1-methylaminocarbonylspiro(indoline-3,4'-piperid-1'-yl)

i) a 1-ethoxycarbonylspiro(indoline-3,4'-piperid-1'-yl)

j) a 1-ethanesulfonylspiro(indoline-3,4'-piperid-1'-yl)

k) a 1-isopropanesulfonylspiro(indoline-3,4'-piperid-1'-yl)

l) a 1'-methyl-1-methanesulfonylspiro(indoline-3,4'-piperidinio-1')iodide

m) a 1-(2-aminoacetyl)spiro(indoline-3,4'-piperid-1'-yl)

n) a 1-methylspiro(indol-2-one-3,4'-piperid-1'-yl)

o) a 2-methylspiro(isoindol-1-one-3,4'-piperid-1'-yl)

p) a spiro(2-oxotetrahydroquinoline-4,4-piperid-1'-yl)

q) a 1-methylspiro(2-oxotetrahydroquinoline-4,4'-piperid-1'-yl)

r) a spiro(2,3-dihydrobenzothiophene-3,4'-piperid-1'-yl)

s) a 5-fluorospiro(2,3-dihydrobenzofiran-3,4'-piperid-1'-yl)

t) a spiro(2,3-dihydrobenzofuran-3,4'-piperid-1'-yl)

u) a spiro(2,3-dihydrobenzothiophene-3,4'-piperid-1'-yl)1-oxide

v) a spiro(2,3-dihydrobenzothiophene-3,4'-piperid-1'-yl)1,1-dioxide

w) a 5-fluoro-1-methanesulfonylspiro(indoline-3,4'-piperid-1'-yl)

x) a 1-methanesulfonyl-5-methoxyspiro(indoline-3,4'-piperid-1'-yl)

y) a 1-methanesulfonyl-5-methylspiro(indoline-3,4'-piperid-1'-yl)

z) a 5-chloro-1-methanesulfonylspiro(indoline-3,4'-piperid-1'-yl)

aa) a 7-fluoro-1-methanesulfonylspiro(indoline-3,4'-piperid-1'-yl)

ab) a 1-acetyl-5-fluorospiro(indoline-3,4'-piperid-1'-yl)

ac) a 1-acetyl-5-chlorospiro(indoline-3,4'-piperid-1'-yl)

ad) a 1-acetyl-5-methylspiro(indoline-3,4'-piperid-1'-yl)

ae) a 1-acetyl-6-fluorospiro(indoline-3,4'-piperid-1'-yl)

af) a 1-acetyl-4-fluorospiro(indoline-3,4'-piperid-1'-yl)

ag) a 1-(N,N-dimethylcarbarnoyl)spiro(indoline-3,4'-piperid-1'-yl);

R₁ and R₂ together form a group --(CH₂)₃ -- or --(CH₂)₄ --;

Ar₁ is a 3,4-dichlorophenyl;

Z═Z'; and

T and A are as defined above for (I),

and their salts, especially pharmaceutically acceptable salts, areparticularly preferred.

When B is a group B₈, W₁₇ is advantageously a direct bond or a methylenegroup, preferably a direct bond, W₁₈ is an oxo, thioxo, imino,methylimino or ethylimino group, preferably an oxo or thioxo group, W₁₉is an oxy or thio group or a group NH, preferably an oxy group or agroup NH, and W₂₀ is an ethylene, cis-vinylene or trimethylene group.Consequently the compounds of formula (I) in which B is B₈ and W₁₇, W₁₈,W₁₉ and W₂₀ are as just defined, and their salts, especiallypharmaceutically acceptable salts, are advantageous products.

The compounds of this subclass of formula (I) in which simultaneously:

B is a group B₈ in which: W₁₇ is a direct bond, W₁₈ is an oxo or thioxogroup, W₁₉ is an oxy group or a group NH and W₂₀ is an ethylene ortrimethylene group;

R₁ and R₂ together form a group --(CH₂)₃ -- or --(CH₂)₄ --;

Ar₁ is a 3,4-dichlorophenyl;

Z═Z'; and

T and A are as defined above for (I),

and their salts, especially pharmaceutically acceptable salts, areparticularly preferred.

Another group of preferred compounds of the invention consists of thecompounds of formula (I) in which R₁, R₂, Ar₁, T, A and Z are as definedabove for (I) and B is the group B₉.

The particularly preferred compounds of formula (I) are those in whichsimultaneously:

B is a group B₉ in which: X₂ is a group --COOR₆₈ or a group--C(═W₂₄)NR₇₀ R₇₁ and W₂₁, W₂₂ and W₂₃, together with the nitrogen atom,form a 2-oxopiperidino group or a 2-oxoperhydropyrimidin-1-yl group;

R₁ and R₂ together form a group --(CH₂)₃ -- or --(CH₂)₄ --;

Ar₁ is a 3,4-dichlorophenyl;

Z═Z'; and

T and A are as defined above for (I),

and their salts, especially pharmaceutically acceptable salts.

Another group of preferred compounds of the invention consists of thecompounds of formula (I) in which R₁, R₂, Ar₁, T, A and Z are as definedabove for (I) and B is the group B₁₀.

The particularly preferred compounds of formula (I) are those in whichsimultaneously:

B is a group B₁₀ ;

R₁ and R₂ together form a group --(CH₂)₃ -- or --(CH₂)₄ --;

Ar₁ is a 3,4-dichlorophenyl;

Z═Z'; and

T and A are as defined above for (I),

and their salts, especially pharmaceutically acceptable salts.

The more particularly preferred compounds of formula (I) are those inwhich simultaneously:

B is a group B₁₀ in which J₆ is a group ##STR44## in which: W₂₅ is apiperid-1-yl and X₁ is a hydrogen, or W₂₅ is an azetidin-1-yl, apyrrolidin-1-yl, a piperid-1-yl, a morpholin4-yl, a thiomorpholin-4-ylor a perhydroazepin-1-yl and X₁ is a carbamoyl;

R₁ and R₂ together form a group --(CH₂)₃ --;

Ar₁ is a 3,4-dichlorophenyl;

T is a group --CO--; and

A is a direct bond,

and their salts, especially pharmaceutically acceptable salts.

Another group of preferred compounds of the invention are those of theformula ##STR45## in which: Ar'₁ is a phenyl which is unsubstituted ormonosubstituted or polysubstituted by a substituent selected from ahalogen atom, a hydroxyl, a (C₁ -C₄)alkoxy, a (C₁ -C₄)-alkyl, atrifluoromethyl and a methylenedioxy, said substituents being identicalor different;

A' is a direct bond or a group --CH₂ --;

Z' is as defined above; and

B_(a) is a group B_(1a) of the formula ##STR46## in which J_(1a) is agroup ##STR47## in which: x is zero;

Ar_(2a) is a phenyl which is unsubstituted or monosubstituted orpolysubstituted by a substituent selected from a halogen atom, ahydroxyl, a (C₁ -C₄)alkoxy, a (C₁ -C₄)alkyl, a trifluoromethyl and amethylenedioxy, said substituents being identical or different; and

X_(1a) is a group selected from:

hydrogen;

(C₁ -C₇)alkyl;

--(CH₂)_(m) --OR₄ in which m is two and R₄ is a hydrogen or a (C₁-C₇)alkyl;

--(CH₂)_(m) --OCOR₅ in which:

m is two and R₅ is a hydrogen; a (C₁ -C₇)alkyl; a (C₃ -C₇)cycloalkylwhich is unsubstituted or substituted by one or more methyls; a phenyl;or a pyridyl; or

m is zero or one and R₅ is a (C₃ -C₇)cycloalkyl which is unsubstitutedor substituted by one or more methyls; a phenyl; or a pyridyl;

--(CH₂)_(m) --OCONH(C₁ -C₇)alkyl in which m is zero or two;

--O--CH₂ --CH₂ --OR₆ in which R₆ is a hydrogen; a (C₁ -C₇)alkyl; aformyl; or a (C₁ -C₇)alkylcarbonyl;

--(CH₂)_(n) --SR₇ in which n is zero or one and R₇ is a hydrogen or a(C₁ -C₇)alkyl;

--CH₂ --S(O)_(j) -(C₁ -C₇)alkyl in which j is one or two;

--NR₈ R₉ in which R₈ and R₉, together with the nitrogen atom to whichthey are bonded, form a piperazine heterocycle which is unsubstituted orsubstituted in the 4-position by a (C₁ -C₄)alkyl;

--(CH₂)_(p) --NR₁₀ R₁₁ in which p is two and R₁₀ and R₁₁ are eachindependently a hydrogen or a (C₁ -C₇)alkyl; R₁₁ can also be a (C₃-C₇)cycloalkylmethyl or a benzyl;

--NR₁₂ COR₁₃ in which R₁₂ is a hydrogen or a (C₁ -C₇)alkyl and R₁₃ is avinyl, a furyl, a thienyl, a pyrrolyl or an imidazolyl;

--NR₁₄ COCOR₁₅ in which R₁₄ is a hydrogen or a (C₁ -C₇)alkyl and R₁₅ isa (C₁ -C₄)alkoxy;

--(CH₂)_(p) --NR₁₄ C(═W₁)R₁₆ in which p is two, W₁ is an oxygen atom ora sulfur atom, R₁₄ is a hydrogen or a (C₁ -C₇)alkyl and R₁₆ is ahydrogen; a (C₁ -C₇)alkyl; a (C₃ -C₇)cycloalkyl which is unsubstitutedor substituted by one or more methyls; a phenyl; a benzyl; a vinyl; apyridyl; a furyl; a thienyl; a pyrrolyl; or an imidazolyl; or p is one,W₁ is a sulfur atom and R₁₄ and R₁₆ are as just defined, or W₁ is anoxygen atom, R₁₄ is as just defined and R₁₆ is a vinyl, a furyl, athienyl, a pyrrolyl or an imidazolyl;

--(CH₂)_(m) --NR₁₄ COOR₁₇ in which m is two, R₁₄ is a hydrogen or a (C₁-C₇)alkyl and R₁₇ is a (C₁ -C₇)alkyl or a phenyl;

--(CH₂)_(m) --NR₁₄ SO₂ R₁₈ in which m is two, R₁₄ is a hydrogen or a (C₁-C₇)alkyl and R₁₈ is a (C₁ -C₇)alkyl; an amino which is free orsubstituted by one or two (C₁ -C₇)alkyls; or a phenyl which isunsubstituted or monosubstituted or poly-substituted by a substituentselected from a halogen atom, a (C₁ -C₇)alkyl, a trifluoromethyl, ahydroxyl, a (C₁ -C₇)alkoxy, a carboxyl, a (C₁ -C₇)alkyl-carbonyloxy, acyano, a nitro and an amino which is free or substituted by one or two(C₁ -C₇)alkyls, said substituents being identical or different;

--(CH₂)_(m) --NR₁₄ C(═W₁)NR₁₉ R₂₀ in which m is two, W₁ is an oxygenatom or a sulfur atom, R₁₄ is a hydrogen or a (C₁ -C₇)alkyl and R₁₉ andR₂₀ are each independently a hydrogen or a (C₁ -C₇)alkyl; R₂₀ can alsobe a (C₃ -C₇)cycloalkyl; a (C₃ -C₇)cycloalkylmethyl; a hydroxyl; a (C₁-C₄)alkoxy; a benzyl; a phenyl; or a (C₁ -C₇)alkyl substituted by ahydroxyl, a (C₁ -C₃)alkoxy, a phenyl, a carboxyl, a (C₁-C₃)alkoxycarbonyl or a carbamoyl which is unsubstituted or substitutedby one or two (C₁ -C₇)alkyls; or R₁₉ and R₂₀, together with the nitrogenatom to which they are bonded, form a heterocycle selected fromazetidine, pyrrolidine, piperidine, morpholine, thiomorpholine,perhydroazepine and piperazine which is unsubstituted or substituted inthe 4-position by a (C₁ -C₄)alkyl; or m is zero or one, W₁ is a sulfuratom and R₁₄, R₁₉ and R₂₀ are as just defined, or W₁ is an oxygen atom,R₁₄ and R₁₉ are each independently a hydrogen or a (C₁ -C₇)alkyl and R₂₀is a (C₁ -C₇)alkyl substituted by a hydroxyl, a (C₁ -C₃)alkoxy, aphenyl, a carboxyl, a (C₁ -C₃)alkoxycarbonyl or a carbamoyl which isunsubstituted or substituted by one or two (C₁ -C₇)alkyls; or R₁₉ andR₂₀, together with the nitrogen atom to which they are bonded, form apiperazine heterocycle which is unsubstituted or substituted in the4-position by a (C₁ -C₄)alkyl;

--(CH₂)_(n) --COOR₂₁ in which n is one and R₂₁ is a hydrogen or a (C₁-C₇)alkyl; or n is zero and R₂₁ is a hydrogen;

--(CH₂)_(n) --C(═W₁)NR₁₉ R₂₀ in which n is one, W₁ is an oxygen atom ora sulfur atom and R₁₉ and R₂₀ are each independently a hydrogen or a (C₁-C₇)alkyl; R₂₀ can also be a (C₃ -C₇)cycloalkyl; a (C₃-C₇)cycloalkylmethyl; a hydroxyl; a (C₁ -C₄)alkoxy; a benzyl; a phenyl;or a (C₁ -C₇)alkyl substituted by a hydroxyl, a (C₁ -C₃)alkoxy, aphenyl, a carboxyl, a (C₁ -C₃)alkoxycarbonyl or a carbamoyl which isunsubstituted or substituted by one or two (C₁ -C₇)alkyls; or R₁₉ andR₂₀, together with the nitrogen atom to which they are bonded, form aheterocycle selected from azetidine, pyrrolidine, piperidine,morpholine, thiomorpholine, perhydroazepine and piperazine which isunsubstituted or substituted in the 4-position by a (C₁ -C₄)alkyl; and nis zero, W₁ is a sulfur atom and R₁₉ and R₂₀ are as just defined, or W₁is an oxygen atom, R₁₉ is a hydrogen or a (C₁ -C₇)alkyl and R₂₀ is a (C₁-C₇)alkyl substituted by a hydroxyl, a (C₁ -C₃)alkoxy, a phenyl, acarboxyl, a (C₁ -C₃)alkoxycarbonyl or a carbamoyl which is unsubstitutedor substituted by one or two (C₁ -C₇)alkyls; or R₁₉ and R₂₀, togetherwith the nitrogen atom to which they are bonded, form a piperazineheterocycle which is unsubstituted or substituted in the 4-position by a(C₁ -C₄)alkyl;

--CO--NR₂₂ NR₂₃ R₂₄ in which R₂₂ is a hydrogen or a (C₁ -C₇)alkyl andR₂₃ and R₂₄ are each independently a hydrogen or a (C₁ -C₇)alkyl;##STR48## in which R₂₅ is a hydrogen or a (C₁ -C₇)alkyl and R₂₆ and R₂₇are each independently a hydrogen or a (C₁ -C₇)alkyl; R₂₇ can also be aformyl or a (C₁ -C₇)alkylcarbonyl; and ##STR49## and their salts,especially pharmaceutically acceptable salts.

Among these compounds, those of the formula ##STR50## in which: B'_(a)is a group B'_(1a) of the formula ##STR51## in which J'_(1a) is a group##STR52## in which: x is zero;

Ar_(2a) is as defined for a compound of formula (Ia); and

X'_(1a) is a group selected from:

--O--CH₂ --CH₂ --OR₆ in which R₆ is a hydrogen; a (C₁ -C₇)alkyl; aformyl; or a (C₁ -C₇)alkylcarbonyl;

--NR₁₂ COR₁₃ in which R₁₂ is a hydrogen or a (C₁ -C₇)alkyl and R₁₃ is avinyl, a furyl, a thienyl, a pyrrolyl or an imidazolyl;

--NR₁₄ COCOR₁₅ in which R₁₄ is a hydrogen or a (C₁ -C₇)alkyl and R₁₅ isa (C₁ -C₄)alkoxy;

--(CH₂)_(p) --NR₁₄ C(═W₁)R₁₆ in which p is one, W₁ is an oxygen atom,R₁₄ is a hydrogen or a (C₁ -C₇)alkyl and R₁₆ is a vinyl, a furyl, athienyl, a pyrrolyl or an imidazolyl;

--(CH₂)_(m) --NR₁₄ C(═W₁)NR₁₉ R₂₀ in which m is zero, W₁ is an oxygenatom, R₁₄ is a hydrogen or a (C₁ -C₇)alkyl, R₁₉ is a hydrogen or a (C₁-C₇)alkyl and R₂₀ is a (C₁ -C₇)alkyl substituted by a hydroxyl, a (C₁-C₃)alkoxy, a phenyl, a carboxyl, a (C₁ -C₃)alkoxycarbonyl or acarbamoyl which is unsubstituted or substituted by one or two (C₁-C₇)alkyls;

--CO--NR₂₂ --NR₂₃ R₂₄ in which R₂₂ is a hydrogen or a (C₁ -C₇)alkyl andR₂₃ and R₂₄ are each independently a hydrogen or a (C₁ -C₇)alkyl;##STR53## in which R₂₅ is a hydrogen or a (C₁ -C₇)alkyl and R₂₆ and R₂₇are each independently a hydrogen or a (C₁ -C₇)alkyl; R₂₇ can also be aformyl or a (C₁ -C₇)alkylcarbonyl; and ##STR54## and their salts,especially pharmaceutically acceptable salts, are particularlypreferred.

Among these compounds, those of the formula ##STR55## in which: X"_(1a)is a group selected from:

--O--CH₂ --CH₂ --OR₆ in which R₆ is a hydrogen; a (C₁ -C₇)alkyl; aformyl; or a (C₁ -C₇)alkylcarbonyl, preferably a hydrogen or an acetyl;

--NR₁₂ COR₁₃ in which R₁₂ is a hydrogen or a (C₁ -C₇)alkyl, preferably ahydrogen, and R₁₃ is a vinyl, a furyl, a thienyl, a pyrrolyl or animidazolyl, preferably a furyl or a thienyl;

--NR₁₄ COCOR₁₅ in which R₁₄ is a hydrogen or a (C₁ -C₇)alkyl, preferablya hydrogen, and R₁₅ is a (C₁ -C₄)alkoxy, preferably an ethoxy; and##STR56## in which R₂₅ is a hydrogen or a (C₁ -C₇)alkyl, preferably ahydrogen, and R₂₆ and R₂₇ are each independently a hydrogen or a (C₁-C₇)alkyl; R₂₇ can also be a formyl or a (C₁ -C₇)alkylcarbonyl; R₂₆ andR₂₇ are preferably a hydrogen; and ##STR57## and their salts, especiallypharmaceutically acceptable salts, are more particularly preferred.

Another group of preferred compounds of the invention are those of theformula ##STR58## in which: Ar'₁ is a phenyl which is unsubstituted ormonosubstituted or polysubstituted by a substituent selected from ahalogen atom, a hydroxyl, a (C₁ -C₄)alkoxy, a (C₁ -C₄)-alkyl, atrifluoromethyl and a methylenedioxy, said substituents being identicalor different;

A' is a direct bond or a group --CH₂ --;

Z' is as defined above; and

B_(b) is a group B_(1b) of the formula ##STR59## in which J_(1b) is agroup ##STR60## in which: x is one;

Ar_(2a) is a phenyl which is unsubstituted or monosubstituted orpolysubstituted by a substituent selected from a halogen atom, ahydroxyl, a (C₁ -C₄)alkoxy, a (C₁ -C₄)alkyl, a trifluoromethyl and amethylenedioxy, said substituents being identical or different; and

X_(1b) is a group selected from:

hydrogen;

(C₁ -C₇)alkyl;

formyl;

(C₁ -C₇)alkylcarbonyl;

--(CH₂)_(m) --OR₄ ;

--(CH₂)_(m) --OCOR₅ ;

--(CH₂)_(m) --OCONH-(C₁ -C₇)alkyl;

--O--CH₂ CH₂ --OR₆ ;

--(CH₂)_(n) --SR₇ ;

--CH₂ --S(O)_(j) -(C₁ -C₇)alkyl;

--NR₈ R₉ ;

--(CH₂)_(p) --NR₁₀ R₁₁ ;

--NR₁₂ COR₁₃ ;

--NR₁₄ COCOR₁₅ ;

--(CH₂)_(p) --NR₁₄ C(═W₁)R₁₆ ;

--(CH₂)_(m) --NR₁₄ COOR₁₇ ;

--(CH₂)_(m) --NR₁₄ SO₂ R₁₈ ;

--(CH₂)_(m) --NR₁₄ C(═W₁)NR₁₉ R₂₀ ;

--(CH₂)_(n) --COOR₂₁ ;

--(CH₂)_(n) --C(═W₁)NR₁₉ R₂₀ ;

--CO--NR₂₂ --NR₂₃ R₂₄ ;

--CN; ##STR61## or X_(1b) forms a double bond between the carbon atom towhich it is bonded and the adjacent carbon atom of the piperidine ring,

in which groups:

m is zero, one or two;

n is zero or one;

p is one or two;

j is one or two;

W₁ is an oxygen atom or a sulfur atom;

R₄ is a hydrogen or a (C₁ -C₇)alkyl;

R₅ is a hydrogen; a (C₁ -C₇)alkyl; a (C₃ -C₇)cycloalkyl which isunsubstituted or substituted by one or more methyls; a phenyl; or apyridyl;

R₆ is a hydrogen; a (C₁ -C₇)alkyl; a formyl; or a (C ₁-C₇)alkylcarbonyl;

R₇ is a hydrogen or a (C₁ -C₇)alkyl;

R₈ and R₉ are each independently a hydrogen or a (C₁ -C₇)alkyl; R₉ canalso be a (C₃ -C₇)cycloalkylmethyl, a benzyl or a phenyl;

or R₈ and R₉, together with the nitrogen atom to which they are bonded,form a heterocycle selected from azetidine, pyrrolidine, piperidine,morpholine, thio-morpholine, perhydroazepine and piperazine which isunsubstituted or substituted in the 4-position by a (C₁ -C₄)alkyl;

R₁₀ and R₁₁ are each independently a hydrogen or a (C₁ -C₇)alkyl; R₁₁can also be a (C₃ -C₇)cycloalkylmethyl or a benzyl;

R₁₂ is a hydrogen or a (C₁ -C₇)alkyl;

R₁₃ is a hydrogen; a (C₁ -C₇)alkyl; a (C₃ -C₇)cycloalkyl which isunsubstituted or substituted by one or more methyls; a phenyl; a benzyl;a vinyl; a pyridyl; a fuiyl; a thienyl; a pyrrolyl; or an imidazolyl;

or R₁₂ and R₁₃ together are a group --(CH₂)_(u) -- in which u is threeor four;

R₁₄ is a hydrogen or a (C₁ -C₇)alkyl;

R₁₅ is a (C₁ -C₄)alkoxy;

R₁₆ is a hydrogen; a (C₁ -C₇)alkyl; a (C₃ -C₇)cycloalkyl which isunsubstituted or substituted by one or more methyls; a phenyl; a benzyl;a vinyl; a pyridyl; a furyl; a thienyl; a pyrrolyl; or an imidazolyl;

R₁₇ is a (C₁ -C₇)alkyl or a phenyl;

R₁₈ is a (C₁ -C₇)alkyl; an amino which is free or substituted by one ortwo (C₁ -C₇)alkyls; or a phenyl which is unsubstituted ormonosubstituted or poly-substituted by a substituent selected from ahalogen atom, a (C₁ -C₇)alkyl, a tri-fluoromethyl, a hydroxyl, a (C₁-C₇)alkoxy, a carboxyl, a (C₁ -C₇)alkoxycarbonyl, a (C₁-C₇)alkylcarbonyloxy, a cyano, a nitro and an amino which is free orsubstituted by one or two (C₁ -C₇)alkyls, said substituents beingidentical or different;

R₁₉ and R₂₀ are each independently a hydrogen or a (C₁ -C₇)alkyl; R₂₀can also be a (C₃ -C₇)cycloalkyl; a (C₃ -C₇)cycloalkylmethyl; ahydroxyl; a (C₁ -C₄)alkoxy; a benzyl; a phenyl; or a (C₁ -C₇)alkylsubstituted by a hydroxyl, a (C₁ -C₃)alkoxy, a phenyl, a carboxyl, a (C₁-C₃)alkoxycarbonyl or a carbamoyl which is unsubstituted or substitutedby one or two (C₁ -C₇)alkyls;

or R₁₉ and R₂₀, together with the nitrogen atom to which they arebonded, form a heterocycle selected from azetidine, pyrrolidine,piperidine, morpholine, thio-morpholine, perhydroazepine and piperazinewhich is unsubstituted or substituted in the 4-position by a (C₁-C₄)alkyl;

R₂₁ is a hydrogen or a (C₁ -C₇)alkyl;

R₂₂ is a hydrogen or a (C₁ -C₇)alkyl;

R₂₃ and R₂₄ are each independently a hydrogen or a (C₁ -C₇)alkyl;

R₂₅ is a hydrogen or a (C₁ -C₇)alkyl; and

R₂₆ and R₂₇ are each independently a hydrogen or a (C₁ -C₇)alkyl; R₂₇can also be a formyl or a (C₁ -C₇)alkylcarbonyl,

with the proviso that:

when Ar'₁ is the 3,4-dichlorophenyl group and A'--Z' is the3-methoxybenzyl group, B_(b) is the group B_(1b) of the formula##STR62## in which J_(1b) is the group ##STR63## in which x is one,Ar_(2a) is a phenyl group and X_(1b) is other than hydrogen, and theirsalts, especially pharmaceutically acceptable salts.

Among these compounds, those of the formula ##STR64## in which: B'_(b)is a group B'_(1b) of the formula ##STR65## in which J'_(1b) is a group##STR66## in which: x is one;

Ar_(2a) is as defined for a compound of formula (Ib); and

X'_(1b) is as group selected from:

(C₁ -C₇)alkyl;

--(CH₂)_(m) --OR₄ in which m is one or two and R₄ is a hydrogen or a (C₁-C₇)alkyl;

--(CH₂)_(m) --OCOR₅ in which:

m is zero and R₅ is a (C₃ -C₇)cycloalkyl which is unsubstituted orsubstituted by one or more methyls; a phenyl; or a pyridyl; or

m is one or two and R₅ is a hydrogen; a (C₁ -C₇)alkyl; a (C₃-C₇)cycloalkyl which is unsubstituted or substituted by one or moremethyls; a phenyl; or a pyridyl;

--(CH₂)_(m) --OCONH-(C₁ -C₇)alkyl in which m is zero, one or two;

--O--CH₂ --CH₂ --OR₆ in which R₆ is a hydrogen; a (C₁ -C₇)alkyl; aformyl; or a (C₁ -C₇)alkylcarbonyl;

--(CH₂)_(n) --SR₇ in which n is zero or one and R₇ is a hydrogen or a(C₁ -C₇)alkyl;

--CH₂ --S(O)_(j) -(C₁ -C₇)alkyl in which j is one or two;

--NR₈ R₉ in which R₈ is a hydrogen or a (C₁ -C₇)alkyl and R₉ is a (C₃-C₇)cycloalkylmethyl or a benzyl; or R₈ and R₉, together with thenitrogen atom to which they are bonded, form a heterocycle selected fromazetidine, thiomorpholine, perhydroazepine and piperazine which isunsubstituted or substituted in the 4-position by a (C₁ -C₄)alkyl;

--(CH₂)_(p) --NR₁₀ R₁₁ in which p is one or two and R₁₀ and R₁₁ are eachindependently a hydrogen or a (C₁ -C₇)alkyl; R₁₁ can also be a (C₃-C₇)cycloalkylrnethyl or a benzyl;

--NR₁₂ COR₁₃ in which R₁₂ is a hydrogen or a (C₁ -C₇)alkyl and R₁₃ is a(C₃ -C₇)-cycloalkyl which is unsubstituted or substituted by one or moremethyls; a phenyl; a benzyl; a vinyl; a pyridyl; a furyl; a thienyl; apyrrolyl; or an imidazolyl; or R₁₂ and R₁₃ together are a group--(CH₂)_(u) -- in which u is three or four;

--NR₁₄ COCOR₁₅ in which R₁₄ is a hydrogen or a (C₁ -C₇)alkyl and R₁₅ isa (C₁ -C₄)alkoxy;

--(CH₂)_(p) --NR₁₄ C(═W₁)R₁₆ in which p is one or two, W₁ is an oxygenatom or a sulfur atom, R₁₄ is a hydrogen or a (C₁ -C₇)alkyl and R₁₆ is ahydrogen; a (C₁ -C₇)alkyl; a (C₃ -C₇)cycloalkyl which is unsubstitutedor substituted by one or more methyls; a phenyl; a benzyl; a vinyl; apyridyl; a firyl; a thienyl; a pyrrolyl; or an imidazolyl;

--(CH₂)_(m) --NR₁₄ COOR₁₇ in which m is zero, one or two, R₁₄ is ahydrogen or a (C₁ -C₇)alkyl and R₁₇ is a (C₁ -C₇)alkyl or a phenyl;

--(CH₂)_(m) --NR₁₄ SO₂ R₁₈ in which m is zero, one or two, R₁₄ is ahydrogen or a (C₁ -C₇)alkyl and R₁₈ is a (C₁ -C₇)alkyl; an amino whichis free or substituted by one or two (C₁ -C₇)alkyls; or a phenyl whichis unsubstituted or monosubstituted or polysubstituted by a substituentselected from a halogen atom, a (C₁ -C₇)alkyl, a trifluoromethyl, ahydroxyl, a (C₁ -C₇)alkoxy, a carboxyl, a (C₁ -C₇)alkoxycarbonyl, a (C₁-C₇)alkylcarbonyloxy, a cyano, a nitro and an amino which is free orsubstituted by one or two (C₁ -C₇)alkyls, said substituents beingidentical or different;

--(CH₂)_(m) --NR₁₄ C(═W₁)NR₁₉ R₂₀ in which m is zero, one or two, W₁ isan oxygen atom or a sulfur atom, R₁₄ is a hydrogen or a (C₁ -C₇)alkyland R₁₉ and R₂₀ are each independently a hydrogen or a (C₁ -C₇)alkyl;R₂₀ can also be a (C₃ -C₇)-cycloalkyl; a (C₃ -C₇)cycloalkylmethyl; ahydroxyl; a (C₁ -C₄)alkoxy; a benzyl; a phenyl; or a (C₁ -C₇)alkylsubstituted by a hydroxyl, a (C₁ -C₃)alkoxy, a phenyl, a carboxyl, a (C₁-C₃)alkoxycarbonyl or a carbamoyl which is unsubstituted or substitutedby one or two (C₁ -C₇)alkyls; or R₁₉ and R₂₀, together with the nitrogenatom to which they are bonded, form a heterocycle selected fromazetidine, pyrrolidine, piperidine, morpholine, thiomorpholine,perhydroazepine and piperazine which is unsubstituted or substituted inthe 4-position by a (C₁ -C₄)alkyl;

--(CH₂)_(n) --COOR₂₁ in which n is one and R₂, is a hydrogen or a (C₁-C₇)alkyl;

--(CH₂)_(n) --C(═W₁)NR₁₉ R₂₀ in which n is zero or one, W₁ is an oxygenatom or a sulfur atom and R₁₉ and R₂₀ are each independently a hydrogenor a (C₁ -C₇)-alkyl; R₂₀ can also be a (C₃ -C₇)cycloalkyl; a (C₃-C₇)cycloalkylmethyl; a hydroxyl; a (C₁ -C₄)alkoxy; a benzyl; a phenyl;or a (C₁ -C₇)alkyl substituted by a hydroxyl, a (C₁ -C₃)alkoxy, aphenyl, a carboxyl, a (C₁ -C₃)alkoxycarbonyl or a carbamoyl which isunsubstituted or substituted by one or two (C₁ -C₇)alkyls; or R₁₉ andR₂₀, together with the nitrogen atom to which they are bonded, form aheterocycle selected from azetidine, pyrrolidine, piperidine,morpholine, thio-morpholine, perhydroazepine and piperazine which isunsubstituted or substituted in the 4-position by a (C₁ -C₄)alkyl;

--CO--NR₂₂ --NR₂₃ R₂₄ in which R₂₂ is a hydrogen or a (C₁ -C₇)alkyl andR₂₃ and R₂₄ are each independently a hydrogen or a (C₁ -C₇)alkyl;##STR67## in which R₂₅ is a hydrogen or a (C₁ -C₇)alkyl and R₂₆ and R₂₇are each independently a hydrogen or a (C₁ -C₇)alkyl; R₂₇ can also be aformyl or a (C₁ -C₇)alkylcarbonyl; and ##STR68## and their salts,especially pharmaceutically acceptable salts, are particularlypreferred.

Among these compounds, those of the formula ##STR69## in which: X"_(1b)is a group selected from:

--(CH₂)_(p) --NR₁₀ R₁₁ in which p is one and R₁₀ and R₁₁ are each ahydrogen;

--(CH₂)_(p) --NR₁₄ C(═W₁)R₁₆ in which p is one, W₁ is an oxygen atom,R₁₄ is a hydrogen or a (C₁ -C₇)alkyl and R₁₆ is a (C₁ -C₇)alkyl,preferably an ethyl;

--(CH₂)_(m) --NR₁₄ COOR₁₇ in which m is zero, R₁₄ is a hydrogen and R₁₇is a (C₁ -C₇)alkyl, preferably an ethyl; and

--(CH₂)_(n) --C(═W₁)NR₁₉ R₂₀ in which n is zero, W₁ is an oxygen atomand R₁₉ and R₂₀, together with the nitrogen atom to which they arebonded, form a heterocycle selected from azetidine, pyrrolidine,piperidine, morpholine, thio-morpholine, perhydroazepine and piperazinewhich is unsubstituted or substituted in the 4-position by a (C₁-C₄)alkyl, preferably pyrrolidine, and their salts, especiallypharmaceutically acceptable salts, are more particularly preferred.

Another group of preferred compounds of the invention are those of theformula ##STR70## in which: Ar'₁ is a phenyl which is unsubstituted ormonosubstituted or polysubstituted by a substituent selected from ahalogen atom, a hydroxyl, a (C₁ -C₄)alkoxy, a (C₁ -C₄)-alkyl, atrifluoromethyl and a methylenedioxy, said substituents being identicalor different;

A' is a direct bond or a group --CH₂ --;

Z' is as defined above; and

B_(c) is a group B_(1c) of the formula ##STR71## in which J_(1c) is agroup ##STR72## in which: x is zero or one;

Ar_(2a) is a phenyl which is unsubstituted or monosubstituted orpolysubstituted by a substituent selected from a halogen atom, ahydroxyl, a (C₁ -C₄)alkoxy, a (C₁ -C₄)alkyl, a trifluoromethyl and amethylenedioxy, said substituents being identical or different; and

X_(1b) is as defined above for a compound of formula (Ib),

and their salts, especially pharmaceutically acceptable salts.

Among these compounds, those of the formula ##STR73## in which: B'_(c)is a group B'_(1c) of the formula ##STR74## in which J'_(1c) is a group##STR75## in which: x is zero or one;

Ar_(2a) is as defined for a compound of formula (Ic); and

X'_(1b) is a group selected from:

(C₁ -C₇)alkyl;

--(CH₂)_(m) --OR₄ in which m is one or two and R₄ is a hydrogen or a (C₁-C₇)alkyl;

--(CH₂)_(m) --OCOR₅ in which m is zero and R₅ is a (C₃ -C₇)cycloalkylwhich is unsubstituted or substituted by one or more methyls; a phenyl;or a pyridyl; or m is one or two and R₅ is a hydrogen; a (C₁ -C₇)alkyl;a (C₃ -C₇)cycloalkyl which is unsubstituted or substituted by one ormore methyls; a phenyl; or a pyridyl;

--(CH₂)_(m) --OCONH-(C₁ -C₇)alkyl in which m is zero, one or two;

--O--CH₂ --CH₂ --OR₆ in which R₆ is a hydrogen; a (C₁ -C₇)alkyl; aformyl; or a (C₁ -C₇)alkylcarbonyl;

--(CH₂)_(n) --SR₇ in which n is zero or one and R₇ is a hydrogen or a(C₁ -C₇)alkyl;

--CH₂ --S(O)_(j) -(C₁ -C₇)alkyl in which j is one or two;

--NR₈ R₉ in which R₈ is a hydrogen or a (C₁ -C₇)alkyl and R₉ is a (C₃-C₇)cycloalkylmethyl or a benzyl; or R₈ and R₉, together with thenitrogen atom to which they are bonded, form a heterocycle selected fromazetidine, thiomorpholine, perhydroazepine and piperazine which isunsubstituted or substituted in the 4-position by a (C₁ -C₄)alkyl;

--(CH₂)_(p) --NR₁₀ R₁₁ in which p is one or two, R₁₀ is a hydrogen or a(C₁ -C₇)alkyl and R₁₁ is a hydrogen, a (C₁ -C₇)alkyl, a (C₃-C₇)cycloalkylmethyl or a benzyl;

--NR₁₂ COR₁₃ in which R₁₂ is a hydrogen or a (C₁ -C₇)alkyl and R₁₃ is a(C₃ -C₇)-cycloalkyl which is unsubstituted or substituted by one or moremethyls; a phenyl; a benzyl; a vinyl; a pyridyl; a furyl; a thienyl; apyrrolyl; or an imidazolyl; or R₁₂ and R₁₃ together form a group--(CH₂)_(u) in which u is three or four;

--NR₁₄ COCOR₁₅ in which R₁₄ is a hydrogen or a (C₁ -C₇)alkyl and R₁₅ isa (C₁ -C₄)alkoxy;

--(CH₂)_(p) --NR₁₄ C(═W₁)R₁₆ in which p is one or two, W₁ is an oxygenatom or a sulfur atom, R₁₄ is a hydrogen or a (C₁ -C₇)alkyl and R₁₆ is ahydrogen; a (C₁ -C₇)alkyl; a (C₃ -C₇)cycloalkyl which is unsubstitutedor substituted by one or more methyls; a phenyl; a benzyl; a vinyl; apyridyl; a furyl; a thienyl; a pyrrolyl; or an imidazolyl;

--(CH₂)_(m) --NR₁₄ COOR₁₇ in which m is zero, one or two, R₁₄ is ahydrogen or a (C₁ -C₇)alkyl and R₁₇ is a (C₁ -C₇)alkyl or a phenyl;

--(CH₂)_(m) --NR₁₄ SO₂ R₁₈ in which m is zero, one or two, R₁₄ is ahydrogen or a (C₁ -C₇)alkyl and R₁₈ is a (C₁ -C₇)alkyl; an amino whichis free or substituted by one or two (C₁ -C₇)alkyls; or a phenyl whichis unsubstituted or monosubstituted or polysubstituted by a substituentselected from a halogen atom, a (C₁ -C₇)alkyl, a trifluoromethyl, ahydroxyl, a (C₁ -C₇)alkoxy, a carboxyl, a (C₁ -C₇)alkoxycarbonyl, a (C₁-C₇)alkylcarbonyloxy, a cyano, a nitro and an amino which is free orsubstituted by one or two (C₁ -C₇)alkyls, said substituents beingidentical or different;

--(CH₂)_(m) --NR₁₄ C(═W₁)NR₁₉ R₂₀ in which m is zero, one or two, W₁ isan oxygen atom or a sulfur atom, R₁₄ is a hydrogen or a (C₁ -C₇)alkyland R₁₉ and R₂₀ are each independently a hydrogen or a (C₁ -C₇)alkyl;R₂₀ can also be a (C₃ -C₇)-cycloalkyl; a (C₃ -C₇)cycloalkylmethyl; ahydroxyl; a (C₁ -C₄)alkoxy; a benzyl; a phenyl; or a (C₁ -C₇)alkylsubstituted by a hydroxyl, a (C₁ -C₃)alkoxy, a phenyl, a carboxyl, a (C₁-C₃)alkoxycarbonyl or a carbamoyl which is unsubstituted or substitutedby one or two (C₁ -C₇)alkyls; or R₁₉ and R₂₀, together with the nitrogenatom to which they are bonded, form a heterocycle selected fromazetidine, pyrrolidine, piperidine, morpholine, thiomorpholine,perhydroazepine and piperazine which is unsubstituted or substituted inthe 4-position by a (C₁ -C₄)alkyl;

--(CH₂)_(n) --COOR₂₁ in which n is one and R₂ is a hydrogen or a (C₁-C₇)alkyl;

--(CH₂)_(n) --C(═W₁)NR₁₉ R₂₀ in which n is zero or one, W₁ is an oxygenatom or a sulfur atom and R₁₉ and R₂₀ are each independently a hydrogenor a (C₁ -C₇)-alkyl; R₂₀ can also be a (C₃ -C₇)cycloalkyl; a (C₃-C₇)cycloalkylmethyl; a hydroxyl; a (C₁ -C₄)alkoxy; a benzyl; a phenyl;or a (C₁ -C₇)alkyl substituted by a hydroxyl, a (C₁ -C₃)alkoxy, aphenyl, a carboxyl, a (C₁ -C₃)alkoxycarbonyl or a carbamoyl which isunsubstituted or substituted by one or two (C₁ -C₇)alkyls; or R₁₉ andR₂₀, together with the nitrogen atom to which they are bonded, form aheterocycle selected from azetidine, pyrrolidine, piperidine,morpholine, thio-morpholine, perhydroazepine and piperazine which isunsubstituted or substituted in the 4-position by a (C₁ -C₄)alkyl;

--CO--NR₂₂ --NR₂₃ R₂₄ in which R₂₂ is a hydrogen or a (C₁ -C₇)alkyl andR₂₃ and R₂₄ are each independently a hydrogen or a (C₁ -C₇)alkyl;##STR76## in which R₂₅ is a hydrogen or a (C₁ -C₇)alkyl and R₂₆ and R₂₇are each independently a hydrogen or a (C₁ -C₇)alkyl; R₂₇ can also be aformyl or a (C₁ -C₇)alkylcarbonyl; and ##STR77## and their salts,especially pharmaceutically acceptable salts, are particularlypreferred.

The following compounds:

1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(pyrrolidin-1-ylcarbonyl)-piperid-1-yl]propyl]piperidine;

1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-(4-piperidinopiperid-1-yl)-propyl]piperidine;

1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-(4-carbamoyl-4-piperidinopiperid-1-yl)propyl]piperidine;

3-[3-[4-(acryloyl-N-methylamino)-4-phenylpiperid-1-yl]propyl-1-benzoyl-3-(3,4-dichlorophenyl)piperidine;

3-[3-[4-(2-aminothiazol-4-yl)-4-phenylpiperid-1-yl]propyl]-1-benzoyl-3-(3,4-dichlorophenyl)piperidine;

3-[3-(4-acetyl-4-benzylpiperid-1-yl)propyl]-1-benzoyl-3-(3,4-dichlorophenyl)piperidine;

3-[3-[4-(acetylamino)-4-benzylpiperid-1-yl]propyl]-1-benzoyl-3-(3,4-dichlorophenyl)piperidine;

1-benzoyl-3-[3-[4-benzyl-4-(propionylaminomethyl)piperid-1-yl]propyl]-3-(3,4-dichlorophenyl)piperidine;

1-benzoyl-3-[3-[4-benzyl-4-(ethoxycarbonylamino)piperid-1-yl]propyl]-3-(3,4-dichlorophenyl)piperidine;

1-benzoyl-3-[3-[4-benzyl-4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]-3-(3,4-dichlorophenyl)piperidine;

1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(dimethylaminocarbonyl)-4-phenylpiperid-1-yl]propyl]perhydroazepine;

1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(2-hydroxyethoxy)4-phenylpiperid-1-yl]propyl]piperidine;

3-[3-[4-(2-acetoxyethoxy)-4-phenylpiperid-1-yl]propyl]-1-benzoyl-3-(3,4-dichlorophenyl)piperidine;

1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(2-furoylamino)-4-phenylpiperid-1-yl]propyl]piperidine;

1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(2-thenoylamino)-4-phenylpiperid-1-yl]propyl]piperidine;

3-(3,4-dichlorophenyl)-1-isonicotinoyl-3-[3-[4-phenyl-4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]piperidine;

1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-spiro(indoline-3,4'-piperid-1'-yl)propyl]piperidine;

1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[1-acetylspiro(indoline-3,4'-piperid-1'-yl)]propyl]piperidine;

3-(3,4-dichlorophenyl)-3-[3-[4-phenyl-4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]-1-(2-thenoyl)piperidine;

3-(3,4-dichlorophenyl)-3-[3-[4-phenyl-4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]-1-(3-thenoyl)piperidine;

3-(3,4-dichlorophenyl)-1-(2-furoyl)-3-[3-[4-phenyl-4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]piperidine;

3-(3,4-dichlorophenyl)-1-(3-furoyl)-3-[3-[4-phenyl-4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]piperidine;

3-[3-[4-(2-amino-1,3,4-oxadiazol-5-yl)-4-phenylpiperid-1-yl]propyl]-1-benzoyl-3-(3,4-dichlorophenyl)piperidine;

1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(ethoxalylamino)-4-phenylpiperid-1-yl]propyl]piperidine;

1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-(4-carbamoyl-4-morpholinopiperid-1-yl)propyl]piperidine;

1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[1-(methoxycarbonyl)spiro-(indoline-3,4'-piperid-1'-yl)]propyl]piperidine;

1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[1-(N,N-dimethylcarbamoyl)spiro-(indoline-3,4'-piperid-1'-yl)]propyl]piperidine;and

1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[1-(methanesulfonyl)spiro(indoline-3,4'-piperid-1'-yl)]propyl]piperidine,

in the form of racemates or one of their (+) or (-) enantiomers, andtheir salts, especially pharmaceutically acceptable salts, are veryparticularly preferred according to the present invention.

The invention further relates, where they exist, to the solvates of thecompounds of the invention and their salts, namely the compounds offormulae (I), (I.sup.•), (I.sup.••), (I.sup.•• a), (Ia), (I'a), (I"a),(Ib), (I'b), (I"b), (Ic) and (I'c) and their salts.

The compounds according to the invention are obtained by known methods,particularly those described in patent applications EP-A474 561 andEP-A-512 901.

One of the methods suitable for obtaining the compounds of formula (I)and their salts is described below.

According to this method:

1) a compound of the formula ##STR78## in which Ar₁, R₁ and R₂ are asdefined for a compound of formula (I) and E is hydrogen or anO-protecting group, is treated:

either with a halogenated derivative of the formula

    Hal--CH.sub.2 --A--Z                                       (III)

in which Hal is a halogen atom, preferably bromine, and A and Z are asdefined for a compound of formula (I), when it is desired to prepare acompound of formula (I) in which T is a group --CH₂ --;

or with a functional derivative of an acid of the formula

    HO--CO--A--Z                                               (IIIa)

in which A and Z are as defined above, when it is desired to prepare acompound of formula (I) in which T is a group --CO--;

or with a chloroformate of the formula

    Cl--COO--A--Z                                              (IIIb)

in which A and Z are as defined above, when it is desired to prepare acompound of formula (I) in which T is group --COO--;

or with an isocyanate of the formula

    O═C═N--A--Z                                        (IIIc)

in which A and Z are as defined above, when it is desired to prepare acompound of formula (I) in which T is a group --CO--NR₃ -- in which R₃is hydrogen;

or with a carbamoyl chloride of the formula ##STR79## in which A and Zare as defined above and R'₃ is a (C₁ -C₄)alkyl, when it is desired toprepare a compound of formula (I) in which T is --CONR₃ -- in which R₃is a (C₁ -C₄)alkyl;

or with a sulfonyl chloride of the formula

    Cl--SO.sub.2 --Z                                           (IIIe)

in which Z is as defined above, when it is desired to prepare a compoundof formula (I) in which --T--A-- is a group --SO₂ --,

to give a compound of the formula ##STR80## 2) the O-protecting group,if present, is removed from the compound of formula (IV), by reactionwith an acid or a base, to give the alcohol of the formula ##STR81## 3)the alcohol (V) is treated with a compound of the formula

    G--SO.sub.2 --Cl                                           (VI)

in which G is a methyl, phenyl, tolyl or trifluoromethyl group, to givea compound of the formula ##STR82## 4) the compound (VII) is reacted:either with a cyclic secondary amine of the formula ##STR83## in whichJ'₁ is: either a group ##STR84## in which Ar₂ and x are as defined for(I) and X'₁ is either X₁ as defined for (I), or a precursor of X₁, itbeing understood that when X'₁ contains a hydroxyl group or an aminogroup, these groups can be protected;

* or a group Ar₂ --CH═C<

in which Ar₂ is as defined for (I);

* or a group ##STR85## in which Ar₂ is as defined for (I); * or a group##STR86## in which Ar₂ is as defined for (I); * or a group ##STR87## inwhich Ar₂, Am₁ and r are as defined for (I); * or a group ##STR88## inwhich Ar₂ and W₂ are as defined for (I); or with a cyclic secondaryamine of the formula ##STR89## in which J₂ is as defined above for (I);or with a cyclic secondary amine of the formula ##STR90## in which J₃ isas defined above for (I); or with a cyclic secondary amine of theformula ##STR91## in which W₄ is as defined above for (I); or with acyclic secondary amine of the formula ##STR92## in which W₆, W₇ and W₈are as defined above for (I); or with a cyclic secondary amine of theformula ##STR93## in which J₄ is as defined above for (I); or with acompound of the formula ##STR94## in which f, g, W₁₂, W₁₃, W₁₄, W₁₅ andW₁₆ are as defined above for (I);

or with a cyclic secondary amine of the formula ##STR95## in which W₁₇,W₁₈, W₁₉ and W₂₀ are as defined above for (I);

or with a cyclic secondary amine of the formula ##STR96## in which J₅ isas defined above for (I); or a cyclic secondary amine of the formula##STR97## in which J'₆ is a group ##STR98## in which W₂₅ is as definedabove for (I) and X'₁ is X₁ as defined for (I), or a precursor of X₁, itbeing understood that when X'₁ contains a hydroxyl group or an aminogroup, these groups can be protected; and

5) after deprotection of the hydroxyl groups or amino groups, ifappropriate, or conversion of X'₁ to X₁, if appropriate, the resultingproduct is optionally converted to one of its salts with a mineral ororganic acid.

In one variant of the method:

1') the nitrogen atom of the compound of formula (II) is protected togive a compound of the formula ##STR99## in which Ar₁, R₁ and R₂ are asdefined for a compound of formula (I), E is hydrogen or an O-protectinggroup and Pr is an N-protecting group such as the trityl,tert-butoxycarbonyl or benzyloxycarbonyl group;

2') the O-protecting group is eventually removed from the compound offormula (XVII), by reaction with an acid or a base, to give the alcoholof the ##STR100## 3') the alcohol (XVIII) is treated with a compound offormula (VI) as defined above to give a compound of the formula##STR101## 4') the compound (XIX) is reacted with a compound of formula(VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh),(VIIIi) or (VIIIj) as defined above to give a compound of the formula##STR102## in which B is as defined for a compound of formula (I), itbeing understood that when B contains a hydroxyl group or an aminogroup, these groups can be protected;

5') the protecting group Pr is selectively removed from the compound offormula (XX) to give the compound of the formula ##STR103## 6') thecompound of formula (XXI) is treated with a compound of formula (III),(IIIa), (IIIb), (IIIc), (IIId) or (IIIe) as defined above; and

7') after deprotection of the hydroxyl groups or amino groups, ifappropriate, the resulting product is optionally converted to one of itssalts with a mineral or organic acid.

More particularly, the compounds of formula (I) and their salts,especially pharmaceutically acceptable salts, are prepared by thevariant of the general method described abovein which:

1.sup.•) a compound of the formula ##STR104## in which G is a methyl,phenyl, tolyl or trifluoromethyl group and Pr is an N-protecting groupsuch as the trityl, tert-butoxycarbonyl or benzyloxycarbonyl group, isreacted with a compound of the formula ##STR105## in which J.sup.• is asdefined for a compound of formula (I.sup.•), to give a compound of theformula ##STR106## 2.sup.•) the protecting group Pr is selectivelyremoved from the compound of formula (XX.sup.•) to give the compound ofthe formula ##STR107## 3.sup.•) the compound of formula (XXI.sup.•) istreated with a functional derivative of an acid of the formula

    HO--CO--Z.sup.•                                      (III.sup.•)

in which Z.sup.• is as defined for a compound of formula (I.sup.•); and

4.sup.•) after deprotection, if appropriate, the resulting product(I.sup.•) is optionally converted to one of its salts with a mineral ororganic acid.

During any one of the steps for the preparation of the compounds offormula (I) or (I.sup.•), and more particularly when using compounds offormula (VIIIa), (VIIIb), (VIIIc), (VIIIe), (VIIIf), (VIIIg), (VIIIh),(VIIIi), (VIIIj) or (VIII.sup.•) or intermediates of formula (II), (IV),(XX), (XXI), (XX.sup.•) or (XXI.sup.•), it may be necessary and/ordesirable to protect the reactive or sensitive functional groups, suchas the amine, hydroxyl or carboxyl groups, present on any one of themolecules in question. This protection can be effected using theconventional protecting groups such as those described in ProtectiveGroups in Organic Chemistry, J. F. W. McOmie, published by Plenum Press,1973, and in Protective Groups in Organic Synthesis, T. W. Greene and P.G. M. Wutts, published by John Wiley & Sons, 1991. The protecting groupscan be removed in an appropriate subsequent step by using the methodsknown to those skilled in the art which do not affect the rest of themolecule in question.

Thus, when E is an O-protecting group, it is selected from theconventional O-protecting groups known to those skilled in the art, forexample tetrahydropyran-2-yl, benzoyl and a (C₁ -C₄)alkylcarbonyl.

The O-protecting groups which may be used to obtain a compound offormula (I) in which X₁ contains a hydroxyl are the conventionalO-protecting groups known to those skilled in the art, as defined abovefor E.

The N-protecting groups which may be used to obtain a compound offormula (I) in which X₁ contains an amino group are the conventionalN-protecting groups known to those skilled in the art, for example thetrityl, methoxytrityl, tert-butoxycarbonyl or benzyloxycarbonyl group.

In step 1) of the method or in step 6') of the variant, when using ahalogenated derivative of formula (I), the reaction is carried out in aninert solvent such as tetrahydrofuran, N,N-dimethylformamide or dimethylsulfoxide, in the presence of a base such as potassium tert-butylate,sodium hydride or lithium diisopropylamide, at a temperature between 0°C. and 80° C.

In step 1), in step 6') or in step 3.sup.•), the functional derivativeof the acid (IIIa) or (III.sup.•) used is the acid itself or one of thefunctional derivatives which react with amines, for example ananhydride, a mixed anhydride, the acid chloride or an activated estersuch as the paranitrophenyl ester.

When using the acid of formula (IIIa) or (III.sup.•) itself, thereaction is carried out in the presence of a coupling agent used inpeptide chemistry, such as 1,3-dicyclohexylcarbodiimide orbenzotriazol-1-yloxytris(dimethylamino) phosphonium hexafluorophosphate,in the presence of a base such as triethylamine orN,N-diisopropylethylamine, in an inert solvent such as dichloromethaneor N,N-dimethylformamide, at a temperature between 0° C. and roomtemperature.

When using an acid chloride, the reaction is carried out in an inertsolvent such as dichloromethane or benzene, in the presence of a basesuch as triethylamine or N-methylmorpholine, at a temperature between-60° C. and room temperature.

When using a chloroformate of formula (IIIb), the reaction is carriedout in an inert solvent such as dichloromethane, at a temperaturebetween 0° C. and room temperature, in the presence of a base such astriethylamine.

When using an isocyanate of formula (IIIc), the reaction is carried outin an inert solvent such as dichloromethane or benzene, at roomtemperature.

When using a carbamoyl chloride of formula (IIId), the reaction iscarried out in a solvent such as toluene or 1,2-dichloroethane, at atemperature between 0° C. and 110° C., in the presence of a base such astriethylamine.

When using a sulfonyl chloride of formula (IIIe), the reaction iscarried out in an inert solvent such as dichloromethane, in the presenceof a base such as triethylamine, at a temperature between -20° C. androom temperature.

In step 2) of the method or in step 2') of the variant, the compound offormula (IV) or the compound of formula (XVII) thus obtained isdeprotected, if appropriate, by the methods known to those skilled inthe art. For example, when E is a tetrahydropyran-2-yl group, thedeprotection is effected by acid hydrolysis using hydrochloric acid in asolvent such as ether, methanol or a mixture of these solvents, or usingpyridinium p-toluenesulfonate in a solvent such as methanol, or elseusing an Amberlys® resin in a solvent such as methanol. The reaction iscarried out at a temperature between room temperature and the refluxtemperature of the solvent. When E is a benzoyl group or a (C₁-C₄)alkylcarbonyl group, the deprotection is effected by hydrolysis inan alkaline medium using, for example, an alkali metal hydroxide such assodium hydroxide, potassium hydroxide or lithium hydroxide, in an inertsolvent such as water, methanol, ethanol, dioxane or a mixture of thesesolvents, at a temperature between 0° C. and the reflux temperature ofthe solvent.

In step 3) of the method or in step 3') of the variant, the reaction ofthe alcohol of formula (V) or the alcohol of formula (XVIII) with asulfonyl chloride of formula (VI) is carried out in the presence of abase such as triethylamine, pyridine, N,N-diisopropylethylamine orN-methylmorpholine, in an inert solvent such as dichloromethane, benzeneor toluene, at a temperature between -20° C. and the reflux temperatureof the solvent.

In step 4) or in step 4'), the compound (VII) or the compound (XIX) thusobtained is reacted with a compound of formula (VIIIa), (VIIIb),(VIIIc), (VIIIe), (VIIIf), (VIIIg), (VIIIh), (VIIIi) or (VIIIj); in step1.sup.•), the compound (XIX.sup.•) is reacted with a compound of formula(VIII.sup.•). The reaction is carried out in an inert solvent such asN,N-dimethylformamide, acetonitrile, methylene chloride, toluene,isopropanol or a mixture of these solvents, in the presence or absenceof a base. When using a base, it is selected from organic bases such astriethylamine, N,N-diisopropylethylamine and N-methylmorpholine, or fromalkali metal carbonates and bicarbonates such as potassium carbonate,sodium carbonate and sodium bicarbonate. In the absence of a base, thereaction is carried out using an excess of the compound of formula(VIIIa), (VIIIb), (VIIIc), (VIIIe), (VIIIf), (VIIIg), (VIIIh), (VIIIi),(VIIIj) or (VIII.sup.•) and optionally in the presence of an alkalimetal iodide such as potassium iodide or sodium iodide. The reaction iscarried out at a temperature between room temperature and 100° C.

In step 5') of the variant or in step 2.sup.•), the compound of formula(XX) obtained or the compound of formula (XX.sup.•) obtained isdeprotected by the methods known to those skilled in the art.

The compounds of formula (I) according to the invention are finallyobtained after deprotection of the hydroxyl groups or amino groups, ifappropriate, or conversion of X'₁ to X₁, if appropriate.

The compounds of formula (I) or (I.sup.•) are isolated in the form ofthe free base or a salt by the conventional techniques.

Thus, when the compound of formula (I) or (I.sup.•) is obtained in theform of the free base, salification is effected by treatment with thechosen acid in an organic solvent. Treatment of the free base, dissolvedfor example in an ether such as diethyl ether, in an alcohol such aspropan-2-ol, in acetone, in dichloromethane or in ethyl acetate, with asolution of the chosen acid in the same solvent gives the correspondingsalt, which is isolated by the conventional techniques.

The hydrochloride, hydrobromide, sulfate, hydrogensulfate,dihydrogen-phosphate, methanesulfonate, oxalate, maleate, fumarate,naphthalene-2-sulfonate and benzenesulfonate, for example, are preparedin this way.

When the reaction has ended, the compounds of formula (I) or (I.sup.•)can be isolated in the form of one of their salts, for example thehydrochloride; in this case, if necessary, the free base can be preparedby neutralization of said salt with a mineral or organic base such assodium hydroxide or triethylamine, or with an alkali metal carbonate orbicarbonate such as sodium or potassium carbonate or bicarbonate.

The compounds of formula (II) are obtained by known methods,particularly those described in patent applications EP-A-0 428 434,EP-A-0 474 561 and EP-A-0 512 901.

In particular, a compound of formula (II) in which R₁ and R₂ togetherform a group --(CH₂)₃ -- and E is a hydrogen can be prepared accordingto SCHEME 1 below: ##STR108##

In step 1, the reaction of a compound of formula (IX) with methylacrylate, in the presence of a base such as Triton® B or1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), gives the compound of formula(X). The reaction is carried out in an inert solvent such as 1,4-dioxaneor tetrahydrofuran, at a temperature between 60° C. and the refluxtemperature of the solvent.

In step 2, the compound of formula (X) is hydrogenated in the presenceof a catalyst such as Raney® nickel to give the compound of formula(XI). The reaction is carried out in an inert solvent such as analkanol, preferably ethanol or 2-methoxyethanol, at a temperaturebetween room temperature and 60° C. and at a pressure betweenatmospheric pressure and 20 bar.

In step 3, the compound of formula (XI) is hydrolyzed in an alkalinemedium using, for example, an alkali metal hydroxide such as sodiumhydroxide or potassium hydroxide, in a solvent such as water, methanolor a mixture of these solvents, at a temperature between roomtemperature and the reflux temperature of the solvent.

The resulting compound of formula (XII) is reduced in step 4 to give theexpected compound of formula (II). The reduction is effected by means ofa reducing agent such as lithium aluminum hydride, diisobutylaluminumhydride or borane in THF, in an inert solvent such as tetrahydrofuran,1,2-dimethoxyethane or toluene, at a temperature between roomtemperature and the reflux temperature of the solvent.

In particular, a compound of formula (II) in which R₁ and R₂ togetherform a group --(CH₂)₄ -- and E is the O-protecting grouptetrahydropyran-2-yl (THP) can be prepared according to SCHEME 2 below:##STR109##

In step 1' of SCHEME 2, a compound of formula (IX) is treated with astrong base, such as sodium hydride, lithium diisopropylamide orpotassium tert-butylate, to give a carbanion, which is reacted withethyl 4-bromobutanoate to give the compound of formula (XIII).

The reaction is carried out in an inert solvent such as an ether (forexample tetrahydrofiran or 1,2-dimethoxyethane), an amide (for exampleN,N-dimethylformamide) or an aromatic hydrocarbon (for example tolueneor xylene), at a temperature between -70° C. and +60° C.

In step 2', the reaction of the compound of formula (XIII) with2-(3-bromopropoxy)tetrahydropyran, in the presence of a strong base suchas sodium hydride, lithium diisopropylamide or potassium tert-butylate,under the operating conditions described in step 1' above, gives thecompound of formula (XIV).

The nitrile derivative of formula (XIV) is reduced in step 3' to givethe primary amine of formula (XV). The reduction is effected by means ofhydrogen, in the presence of a catalyst such as Raney® nickel, in aninert solvent such as an alkanol, for example methanol, by itself ormixed with a saturated solution of ammonia in the same solvent, at atemperature between room temperature and 50° C.

In step 4', the cyclized compound of formula (XVI) is obtained byrefluxing a solution of the compound of formula (XV) in an aromaticsolvent such as toluene or xylene.

In step 5', the compound of formula (XVI) is reduced to give theexpected compound of formula (II). The reduction is effected by means ofa reducing agent such as lithium aluminum hydride, diisobutylaluminumhydride, sodium borohydride or borane in THF, in an inert solvent suchas tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane or toluene, at atemperature between room temperature and the reflux temperature of thesolvent.

The compounds of formula (III), (IIIa), (IIIb), (IIIc), (IIId), (IIIe)or (III.sup.•) are known or are prepared by known methods.

The piperidines of formula (VIIIa) are known or are prepared by knownmethods such as those described in EP-A-0 428 434, EP-A-0 474 561,EP-A-0 512 901 and EP-A-0 515 240.

The piperidines of formula (VIIIa) can also be prepared by methods wellknown to those skilled in the art, such as those described in thefollowing publications:

J. Heterocyclic Chem., 1986, 23, 73-75;

J. Chem. Soc., 1950, 1469;

J. Chem. Soc., 1945, 917;

J. Pharm. Sci., 1972, 61, 1316-1317;

J. Org. Chem., 1957, 22, 1484-1489;

Chem. Ber., 1975, 108, 3475-3482.

The compounds of formula (VIIIa) are generally prepared in a formprotected on the piperidine nitrogen; the compounds of formula (VIIIa)themselves are obtained after a deprotection step.

Different methods of obtaining the compounds of formula (VIIIa),in whichthe different substituents are as defined for formula (I), unlessstipulated otherwise, will be indicated below as examples.

For example, when Ar₂ is a pyrid-2-yl group, X'₁ is hydroxyl and x iszero in a piperidine of formula (VIIIa), 2-bromopyridine is reacted withN-benzylpiperid-4-one in a solvent, in the presence of butyllithium, inorder to prepare N-benzyl-4-hydroxy-4-(pyrid-2-yl)piperidine;4-hydroxy-4-(pyrid-2-yl)piperidine is then obtained by deprotection in abasic medium.

Furthermore, a compound of formula (VIIIa) in which X'₁ is a group--(CH₂)_(m) --OR₄ in which R₄ is hydrogen and m is one or two isprepared by reducing a compound of formula (VIIIa) in which X'₁ is amethoxycarbonyl or, respectively, a methoxycarbonylmethyl by the methoddescribed in Chem. Ber., 1975, 108, 3475-3482.

A compound of formula (VIIIa) in which X'₁ is a group --(CH₂)_(m) --OR₄in which R₄ is a (C₁ -C₇)alkyl can also be prepared by alkylating acompound of formula (VIIIa) in which X'₁ is a group --(CH₂)_(m) --OH bythe methods known to those skilled in the art.

A compound of formula (VIIIa) in which X'₁ is a group --O--CH₂ --CH₂--OR₆ in which R₆ is hydrogen can also be prepared by reacting acompound of formula (VIIIa) in which X'₁ is a benzoyloxy with ethyleneglycol in the presence of an acid such as sulfuric acid.

The compounds of formula (VIIIa) in which X'₁ is a group --O--CH₂ CH₂--OR₆ in which is a (C₁ -C₇)alkyl are prepared by an identical reactionusing a 2-(C₁ -C₇)alkoxyethanol.

The compounds of formula (VIIIa) in which X'₁ is a group --O--CH₂ CH₂--OR₆ in which R₆ is a formyl are prepared by reacting formic acid witha compound of formula (VIIIa) in which X'₁ is a group --O--CH₂ CH₂ --OH.The compounds of formula (VIIIa) in which X'₁ is a group --O--CH₂ CH₂--OR₆ in which R₆ is a (C₁ -C₇)-alkylcarbonyl are prepared by reactionwith a C₂ -C₅ acid chloride in the presence of a base such astriethylamine.

The compounds of formula (VIIIa) in which X'₁ is a group --(CH₂)_(n)--SR₇ or a group --CH₂ --S(O)_(j) --(C₁ -C₇)alkyl are known or areprepared by known methods such as those described in WO 95/12577.

The compounds of formula (VIIIa) in which X'₁ is a group --(CH₂)_(m)--OCOR₅ (R₅ other than hydrogen) are prepared by reacting an acidchloride R₅ COCl (R₅ other than hydrogen) with a compound of formula(VIIIa) in which X'₁ is a group --(CH₂)_(m) --OH, in the presence of abase such as triethylamine.

The compounds of formula (VIIIa) in which X'₁ is a group --(CH₂)_(m)--OCOR₅ in which R₅ is hydrogen are prepared by reacting formic acidwith a compound of formula (VIIIa) in which X'₁ is a group --(CH₂)_(m)--OH.

The compounds of formula (VIIIa) in which X'₁ is a group (C₁-C₇)alkyl-NHCOO--(CH₂)_(m) -- are obtained by reacting a carbamoylchloride, (C₁ -C₇)alkyl-NHCOCl, with the compounds of formula (VIIIa) inwhich X'₁ is a group --(CH₂)_(m) --OH. The same compounds are preparedby reacting an isocyanate, (C₁ -C₇)alkyl-N═C═O, with the compounds offormula (VIIIa) in which X'₁ is a group --(CH₂)_(m) --OH.

The compounds of formula (VIIIa) in which X'₁ is a hydroxyl and whichcarry a protecting group on the piperidine nitrogen can undergo a Ritterreaction with acetonitrile in order to prepare the compounds of formula(VIIIa) in which X'₁ is an acetamido. The compounds of formula (VIIIa)in which X'₁ is a group --NR₈ R₉ in which R₈ and R₉ are each hydrogenare then prepared by hydrolysis in an acid medium.

A compound of formula (VIIIa) in which X'₁ is a group --NR₈ R₉ in whichR₈ and R₉ are each hydrogen can also be prepared by hydrolyzing in astrong acid medium, for example hydrochloric acid, a compound of formula(VIIIa) in which X'₁ is an isocyanato group.

A compound of formula (VIIIa) in which X'₁ is a group --NR₈ R₉ in whichR₈ is hydrogen and R₉ is a (C₁ -C₇)alkyl, or a (C₃ -C₇)cycloalkylmethylor a benzyl, can be prepared by reducing a compound of formula (VIIIa)in which X'₁ is a group --NR₁₂ COR₁₃ in which R₁₂ is hydrogen and R₁₃ isa hydrogen or a (C₁ -C₆)alkyl or, respectively, a (C₃ -C₇)cycloalkyl ora phenyl. The reaction is carried out by means of a reducing agent suchas lithium aluminum hydride, in a solvent such as tetrahydrofuran, atthe reflux temperature of the solvent.

The compounds of formula (VIIIa) in which X'₁ is a group --NR₈ R₉ inwhich R₈ is a (C₁ -C₇)alkyl can be prepared by an identical reactionfrom the compounds of formula (VIIIa) in which X'₁ is a group --NR₁₂COR₁₃ in which R₁₂ is a (C₁ -C₇)alkyl.

A compound of formula (VIIIa) in which X'₁ is a group --NR₈ R₉ in whichR₈ and R₉, together with the nitrogen atom to which they are bonded,form a heterocycle is prepared by applying or adapting Bruylants'reaction (Bull. Soc. Chim. Belges, 1924, 33, 467, and TetrahedronLetters, 1988, 29 (52), 6827-6830).

A compound of formula (VIIIa) in which X'₁ is a group --CH₂ --NR₁₀ R₁₁in which R₁₀ and R₁₁ are each hydrogen is prepared by reducing acompound of formula (VIIIa) in which X'₁ is a cyano. This reduction iseffected by the methods well known to those skilled in the art.

A compound of formula (VIIIa) in which X'₁ is a group --CH₂ --CH₂ --NR₁₀R₁₁ in which R₁₀ and R₁₁ are each a hydrogen is prepared from a compoundof formula (VIIIa) in which X'₁ is a group --CH₂ --CH₂ --OH by applyingor adapting the method described in J. Med. Chem., 1989, 32, 391-396.

The compounds of formula (VIIIa) in which X'₁ is a group --(CH₂)_(p)--NR₁₀ R₁₁ in which R₁₀ is a hydrogen or a (C₁ -C₇)alkyl and R₁₁ is a(C₁ -C₇)alkyl, a (C₃ -C₇)-cycloalkylmethyl or a benzyl can be preparedby reducing a compound of formula (VIIIa) in which X'₁ is a group--(CH₂)_(p) --NR₁₄ C(═W₁)R₁₆ in which R₁₄ is a hydrogen or a (C₁-C₇)alkyl, R₁₆ is a hydrogen, a (C₁ -C₆)alkyl, a (C₃ -C₇)cycloalkyl or aphenyl and W₁ is an oxygen atom.

The compounds of formula (VIIIa) in which X'₁ is a group --NR₁₂ COR₁₃ inwhich R₁₂ is a hydrogen or a (C₁ -C₇)alkyl and R₁₃ is hydrogen orrespectively a (C₁ -C₇)alkyl, an optionally substituted (C₃-C₇)cycloalkyl, a phenyl, a benzyl, a vinyl, a pyridyl, a furyl, athienyl, a pyrrolyl or an imidazolyl are obtained by reacting formicacid in acetic anhydride or, respectively, an appropriate acid chlorideR₁₃ COCl, in the presence of a base such as triethylamine, with acompound of formula (VIIIa) in which X'₁ is a group --NHR₁₂. Inparticular, a compound of formula (VIIIa) in which X'₁ is a group --NR₁₂COR₁₃ in which R₁₃ is an ethyl radical can be prepared by hydrogenating,in the presence of a catalyst such as palladium on charcoal, a compoundof formula (VIIIa) in which X'₁ is an acryloylamino or acryloyl-N-(C₁-C₇)alkylamino group.

A compound of formula (VIIIa) in which X'₁ is a group --NR₁₂ COR₁₃ inwhich R₁₂ and R₁₃ together are a group --(CH₂)₃ -- or --(CH₂)₄ -- isprepared by applying or adapting the method described in J. Med. Chem.,1985, 28, 46-50.

A compound of formula (VIIIa) in which X'₁ is a group --NR₁₄ COCOR₁₅ inwhich R₁₅ is a (C₁ -C₄)alkoxy is prepared by reacting a compound of theformula Cl--COCOR₁₅ with a compound of formula (VIIIa) in which X'₁ is agroup --NHR₁₄.

The compounds of formula (VIIIa) in which X'₁ is a group --(CH₂)_(p)--NR₁₄ C(═W₁)R₁₆ in which W₁ is an oxygen atom, p is 1 or 2, R₁₄ is ahydrogen or a (C₁ -C₇)alkyl and R₁₆ is a hydrogen or respectively a (C₁-C₇)alkyl, a phenyl, a benzyl, a pyridyl, an optionally substituted (C₃-C₇)cycloalkyl, a vinyl, a furyl, a thienyl, a pyrrolyl or an imidazolylare obtained by reacting formic acid in acetic anhydride or,respectively, an appropriate acid chloride R₁₆ COCl, in the presence ofa base such as triethylamine, with a compound of formula (VIIIa) inwhich X'₁ is a group --CH₂ --NHR₁₄ or --CH₂ --CH₂ --NHR₁₄.

A compound of formula (VIIIa) in which X'₁ is a group --(CH₂)_(p) --NR₁₄C(═W₁)R₁₆ in which W₁ is a sulfur atom is obtained from a correspondingcompound of formula (VIIIa) which is protected on the piperidinenitrogen and in which W₁ is an oxygen atom by reaction with phosphoruspentasulfide or with Lawesson's reagent,2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-disphosphetane-2,4-disulfide,followed by deprotection of the piperidine nitrogen.

A compound of formula (VIIIa) in which X'₁ is a group --(CH₂)_(m) --NR₁₄COOR₁₇ is prepared by reacting a chloroformate of the formula ClCOOR₁₇with a compound of formula (VIIIa) in which X'₁ is a group --(CH₂)_(m)--NHR₁₄, in the presence of a base such as triethylamine.

It is also possible to prepare a compound of formula (VIIIa) in whichX'₁ is a group --(CH₂)_(m) --NR₁₄ COOR₁₇ in which m=0 and R₁₄ ishydrogen by reacting a compound R₁₇ OH with a compound of formula(VIIIa) in which X'₁ is an isocyanato group (--N═C═O).

A compound of formula (VIIIa) in which X'₁ is an isocyanato group isprepared from a compound of formula (VIIIa) in which X'₁ is a carboxylgroup by the method described in Organic Synthesis, 51, 48-52.

A compound of formula (VIIIa) in which X'₁ is a group --(CH₂)_(m) --NR₁₄SO₂ R₁₈ is prepared by reacting a sulfonyl chloride ClSO₂ R₁₈ with acompound of formula (VIIIa) in which X'₁ is a group --(CH₂)_(m) --NHR₁₄,in the presence of a base such as triethylamine.

Likewise, the compounds of formula (VIIIa) in which X'₁ is a group--(CH₂)_(m) --NR₁₄ CONR₁₉ R₂₀ in which R₁₉ is a hydrogen and R₂₀ is a(C₁ -C₇)alkyl are prepared by reaction with an isocyanate of the formulaR₂₀ N═C═O in which R₂₀ is a (C₁ -C₇)alkyl.

The compounds of formula (VIIIa) in which X'₁ is a group --(CH₂)_(m)--NR₁₄ CONR₁₉ R₂₀ in which R₁₉ is a (C₁ -C₇)alkyl are prepared byreaction with a carbamoyl chloride of the formula ClCONR₁₉ R₂₀.

A compound of formula (VIIIa) in which X'₁ is a group --(CH₂)_(m) --NR₁₄CONR₁₉ R₂₀ can also be obtained by reacting a compound HNR₁₉ R₂₀ with acompound of formula (VIIIa) in which X'₁ is a group --(CH₂)_(m) --NR₁₄COOR₁₇ in which R₁₇ is a phenyl.

A compound of formula (VIIIa) in which X'₁ is a group --(CH₂)_(m) --NR₁₄CONR₁₉ R₂₀ in which m=0 and R₁₄ is hydrogen can also be prepared byreacting a compound NHR₁₉ R₂₀ with a compound of formula (VIIIa) inwhich X'₁ is an isocyanato group.

A compound of formula (VIIIa) in which X'₁ is a group --(CH₂)_(m) --NR₁₄C(═W₁)NR₁₉ R₂₀ in which W₁ is a sulfur atom is prepared by reacting acompound of formula (VIIIa), protected on the piperidine nitrogen, inwhich X'₁ is a group --(CH₂)_(m) --NR₁₄ CONR₁₉ R₂₀ with phosphoruspentasulfide or with Lawesson's reagent.

A compound of formula (VIIIa) in which X'₁ is a group --CONR₁₉ R₂₀ isprepared by reacting a compound of formula (VIIIa) in which X'₁ is acarboxyl with a compound of formula HNR₁₉ R₂₀ by the methods well knownto those skilled in the art.

Likewise, the compounds of formula (VIIIa) in which X'₁ is a group --CH₂--CONR₁₉ R₂₀ are prepared by reacting a compound of formula (VIIIa) inwhich X'₁ is a group --CH₂ --COOR₂₁ in which R₂₁ is hydrogen with acompound HNR₁₉ R₂₀.

A compound of formula (VIIIa) in which X'₁ is a group --(CH₂)_(n)--C(═W₁)NR₁₉ R₂₀ in which W₁ is a sulfur atom is prepared, by theabove-mentioned methods, from a compound of corresponding formula(VIIIa) in which W₁ is an oxygen atom.

A compound of formula (VIIIa) in which X'₁ is a carboxyl can be preparedby hydrolyzing a compound of formula (VIIIa) in which X'₁ is a cyano bythe methods known to those skilled in the art.

A compound of formula (VIIIa) in which X'₁ is a carboxymethyl can beprepared by the method described in Chem. Ber., 1975, 108, 3475-3482.

A compound of formula (VIIIa) in which X'₁ is a (C₁ -C₇)alkoxycarbonylor a (C₁ -C₇)alkoxycarbonylmethyl can be prepared from a compound offormula (VIIIa) in which X'₁ is a carboxyl or, respectively, acarboxymethyl by means of an esterification reaction by the methods wellknown to those skilled in the art.

In particular, a compound of formula (VIIIa) in which Ar₂ is anoptionally substituted phenyl radical, x is one and X'₁ is a (C₁-C₇)alkoxycarbonyl is prepared by reacting a protected 4-(C₁-C₇)alkoxycarbonylpiperidine with an optionally substituted benzylhalide in the presence of a base such as sodium hydride, potassiumtert-butylate or sodium diisopropylamide, in a solvent such astetra-hydrofiran, N,N-dimethylformamide or dimethyl sulfoxide, at atemperature between -78° C. and room temperature. The expected compoundof formula (VIIIa) is obtained after a deprotection step.

A compound of formula (VIIIa) in which X'₁ is a group --CO--NR₂₂ --NR₂₃R₂₄ is prepared by reacting a hydrazine HNR₂₂ --NR₂₃ R₂₄ with a compoundof formula (VIIIa) in which X'₁ is a chloroformyl.

A compound of formula (VIIIa) in which X'₁ is a group ##STR110## inwhich R₂₆ and R₂₇ are each independently a hydrogen or a (C₁ -C₇)alkylis prepared by reacting a compound of formula (VIIIa) in which X'₁ is agroup ##STR111## in which Hal is a halogen atom, preferably bromine,with a thioureain which one of the amino groups is free or substitutedby one or two (C₁ -C₇)alkyls.

A compound of formula (VIIIa) in which X'₁ is a group ##STR112## inwhich R₂₇ is a formyl or respectively a (C₁ -C₇)alkylcarbonyl isprepared by reacting formic acid in acetic anhydride or, respectively,an acid chloride (C₁ -C₇)alkyl-COCl, in the presence of a base such astriethylamine, with the above compound of formula (VIIIa), protected onthe piperidine nitrogen, in which R₂₇ is hydrogen. The expected compoundis obtained after a deprotection step.

The compound of formula (VIIIa) in which X'₁ is a group ##STR113## inwhich Hal is a bromine atom is obtained by the bromination, by theconventional methods, of a compound of formula (VIIIa) in which X'₁ is agroup --CO--CH₂ --R₂₅.

A compound of formula (VIIIa) in which X'₁ is a group ##STR114## can beprepared by reacting a protected compound of formula (VIIIa) in whichX'₁ is a carbazoyl group (--CONH--NH₂) with cyanogen bromide by themethod described in J. Org. Chem., 1961, 26, 88-95. The compound offormula (VIIIa) in which X'₁ is a carbazoyl group is obtained byreacting hydrazine with a compound of formula (VIIIa) in which X'₁ is achloroformyl, which is itself obtained by reacting thionyl chloride witha compound of formula (VIIIa) in which X'₁ is a carboxyl.

The piperazines of formula (VIIIb) are known or are prepared by knownmethods such as those described in EP-A-0 428 434.

The piperidines of formula (VIIIc) are known or are prepared by knownmethods such as those described in WO 94/10146.

The piperidines of formula (VIIId) are known or are prepared by knownmethods such as those described in EP-A-0 625 509.

The piperidines of formula (VIIIe) are known or are prepared by knownmethods such as those described in EP-A-0 630 887.

The piperidines of formula (VIIIf) are known or are prepared by knownmethods such as those described in WO 94/26735.

The compounds of formula (VIIIg) are known or are prepared by knownmethods such as those described in WO 94/29309.

The piperidines of formula (VIIIh) are known or are prepared by knownmethods such as those described in WO 95/05377.

The piperidines of formula (VIIIi) are known or are prepared by knownmethods such as those described in WO 95/12577.

The piperidines of formula (VIIIj) are known or are prepared by knownmethods.

In particular, the piperidines of formula (VIIIj) in which J'₆ is agroup ##STR115## in which X'₁ is other than hydrogen and W₂₅ is a (C₁-C₇)alkyl or a (C₃ -C₇)cycloalkyl are prepared by the proceduresdescribed above for the preparation of the piperidines of formula(VIIIa).

A piperidine of formula (VIIIj) in which J'₆ is a group ##STR116## inwhich W₂₅ is a group --NR₇₉ R₈₀ and X'₁ is a cyano is prepared by meansof a Strecker reaction between a 1-benzylpiperid4-one and a compound ofthe formula NHR₇₉ R₈₀ in the presence of sodium cyanide. The compound ofexpected formula (VIIIj) is obtained after a deprotection step.Hydrolysis of the cyano group in a strong acid medium by the methodsknown to those skilled in the art gives the corresponding piperidines offormula (VIIIj) in which X'₁ is a carboxyl. The latter compounds can beused to obtain the corresponding piperidines of formula (VIIIj) in whichX'₁ is a (C₁ -C₇)alkoxycarbonyl or a group --CONR₁₉ R₂₀ by the methodsknown to those skilled in the art, for example by means ofesterification or, respectively, by the methods of peptide coupling.

The piperidines of formula (VIII.sup.•) are also known or can beprepared by known methods. In particular, when J.sup.• is a group of thestructure ##STR117## the piperidine of formula (VIII.sup.•) is preparedby one of the methods described above for the compounds of formula(VIIIa) in which X'₁ is a group --CONR₁₉ R₂₀, especially by reacting acarboxylic acid of the formula ##STR118## with an amine of the formulaNHR₁₉ R₂₀.

When J.sup.• is a group of the structure ##STR119## the piperidine offormula (VIII.sup.•) is prepared by methods described in WO 94/29309.

The enantiomers of the compounds according to the invention, of theformula ##STR120## in which: "*" denotes that the carbon atom carryingthis label has the determined (+) or (-) absolute configuration; and

R₁, R₂, Ar₁, T, A, Z and B are as defined for the compounds of formula(I), and their salts with mineral or organic acids, are novel compoundswhich form part of the invention.

The enantiomers of formula (I*) can be isolated by resolution of theracemic mixtures of the compounds of formula (I). It is preferable,however, to resolve the racemic mixtures at the stage of an intermediatewhich can be used to prepare a compound of formula (I), as described inpatent applications EP-A-0 474 561, EP-A-0 512 901, EP-A-0 591 040 andEP-A-0 612 716.

The compounds of formula (I) above also include thosein which one ormore hydrogen, carbon or iodine atoms have been replaced by theirradioactive isotope, for example tritium, carbon 14 or iodine 125. Suchlabeled compounds are useful in research, metabolic or pharmacokineticstudies and in biochemical assays as receptor ligands.

The affinity of the compounds of formula (I) for the tachykininreceptors was evaluated in vitro by means of several biochemical assaysusing radioligands:

1.sup.•) The binding of [¹²⁵ I]BH-SP (substance P labeled with iodine125 using Bolton-Hunter's reagent) to the NK₁ receptors of rat cortex,guinea-pig ileum and human lymphoblastic cells.

2.sup.•) The binding of [¹²⁵ I]His-NK_(A) to the NK₂ receptors of ratbladder or the binding of [¹²⁵ I]NPγ to the NK₂ receptors of guinea-pigileum.

3.sup.•) The binding of [¹²⁵ I]His[MePhe⁷ ]NK_(B) to the NK₃ receptorsof rat cerebral cortex, guinea-pig cerebral cortex and gerbil cerebralcortex and to the human NK₃ cloned receptors expressed by CHO cells(Buell et al., FEBS Letters, 1992, 299, 90-95).

The assays were performed according to X. Emonds-Alt et al. (Eur. J.Pharmacol., 1993, 250 403-413).

The compounds according to the invention strongly inhibit the binding of[¹²⁵ I]His[MePhe⁷ ]NK_(B) to the NK₃ receptors of guinea-pig and gerbilcerebral cortex and to the human NK₃ cloned receptors: the inhibitionconstant Ki is generally less than 5.10⁻⁹ M. For the same compounds, itwas found that the inhibition constant (Ki) for the NK₃ receptors of ratcerebral cortex is generally greater than 10⁻⁸ M and that the inhibitionconstant (Ki) for the NK₂ receptor of rat duodenum and the NK₁ receptorsof rat cortex is generally greater than or equal to 10⁻⁷ M.

The compounds according to the present invention were also evaluated invivo on two animal models.

In the gerbil, a rotational behavior is induced by the intrastriataladministration of the specific NK₃ receptor agonist senktide; it wasfound that a unilateral administration of senktide to gerbil striatumleads to strong contralateral rotations which are inhibited by thecompounds according to the invention, administered eitherintraperitoneally or orally.

This result shows that the compounds according to the invention passthrough the blood-brain barrier and that they are capable of blockingthe characteristic action of the NK₃ receptors in the central nervoussystem. They may thus be used for the treatment of any NK_(B) -dependentpathological condition of the central nervous system, such aspsychiatric diseases, or any pathological condition mediated by the NK₃receptor in the central nervous system, such as psychosomatic diseases.

In the guinea-pig, an intravenous or intracerebroventricular injectionof senktide induces hypertension which is suppressed by the oral orintravenous administration of the compounds according to the invention.

This result shows that the compounds according to the invention act onthe cardiovascular system and that they are capable of blocking thecharacteristic action of the NK₃ receptors in said system, especiallyhypertension (Nakayama et al., Brain Res., 1992, 595, 339-342; Takanoand Kamiya, Asia Pacific J. Pharmacol., 1991, 6, 341-346; Saigo et al.,Neuroscience Letters, 1993, 159, 187-190).

In the guinea-pig, the inhalation of substance P, for example, inducesbronchial hyperreactivity to acetylcholine and hypersensitivity tohistamine, for example in the plasmic extravasation. An NK₃ antagonistblocks these tvo characteristic processes of respiratory pathologicalconditions like asthma.

In these tests, the compounds according to the invention are active atdoses varying from 0.1 mg to 30 mg per kg, administered orally,intravenously or intraperitoneally.

The compounds of the present invention are generally administered indosage units. Said dosage units are preferably formulated intopharmaceutical compositionsin which the active principle is mixed with apharmaceutical excipient.

According to another of its aspects, the present invention relates topharmaceutical compositions containing, as the active principle, acompound of formula (I) or one of its pharmaceutically acceptable saltswhich has a very high affinity for the human NK₃ receptor, said affinitybeing characterized by an inhibition constant Ki generally of less than5.10⁻⁹ M in ligand binding studies.

The compounds of formula (I) and their pharmaceutically acceptable saltscan be used in daily doses of 0.01 to 100 mg per kilogram of body weightof the mammal to be treated, preferably in daily doses of 0.1 to 50mg/kg. In humans the dose can preferably vary from 0.5 to 4000 mg perday, more particularly from 2.5 to 1000 mg, depending on the age of thesubject to be treated or the type of treatment: prophylactic orcurative.

Examples of diseases which can be treated using the compounds and theirpharmaceutically acceptable salts are diseases associated with adysfunction of the dopaminergic systems, such as schizophrenia andParkinson's disease, diseases associated with a dysfunction of thenoradrenergic and serotoninergic systems, such as anxiety, vigilancedisorders and humor disorders, all forms of epileptic disease,particularly grand mal, dementia, neurodegenerative diseases, peripheraldiseasesin which the central nervous system and/or the peripheralnervous system participate via neurokinin B acting as a neurotransmitteror neuromodulator, such as pain, migraine and acute or chronicinflammation, cardiovascular disorders, particularly hypertension,cardiac insufficiency and rhythm disorders, respiratory disorders(asthma, rhinitis, cough, bronchitis, allergy, hypersensitivity),disorders of the gastrointestinal system, such as esophageal ulcer,colitis, stress-related disorders, irritable bowel syndrome (IBS) andacidic secretion, emesis/nausea (following chemotherapy, postoperative,due to travel sickness or due to vestibular disorders), disorders of theurinary system (incontinence, nervous bladder), diseases of the immunesystem (rheumatoid arthritis) and, more generally, any neurokininB-dependent pathological condition.

In the pharmaceutical compositions of the present invention for oral,sublingual, inhalational, subcutaneous, intramuscular, intravenous,transdermal, local or rectal administration, the active principles canbe administered to animals and humans in unit forms of administration,mixed with conventional pharmaceutical carriers. The appropriate unitforms of administration include forms for oral administration, such astablets, gelatin capsules, powders, granules and solutions orsuspensions to be taken orally, forms for sublingual and buccaladministration, forms for subcutaneous, intramuscular, intravenous,intranasal or intraocular administration and forms for rectaladministration.

When a solid composition in the form of tablets is prepared, the mainactive principle is mixed with a pharmaceutical vehicle such as silica,gelatin, starch, lactose, magnesium stearate, talcum, gum arabic or thelike. The tablets can be coated with sucrose, various polymers or otherappropriate substances or else they can be treated so as to have asustained or delayed activity and so as to release a predeterminedamount of active principle continuously.

A preparation in the form of gelatin capsules is obtained by mixing theactive principle with a diluent, such as a glycol or a glycerol ester,and introducing the mixture obtained into soft or hard gelatin capsules.

A preparation in the form of a syrup or elixir can contain the activeprinciple together with a sweetener, which is preferably calorie-free,methylparaben and propylparaben as antiseptics, a flavoring and anappropriate color.

The water-dispersible granules or powders can contain the activeprinciple mixed with dispersants or wetting agents or with suspendingagents such as polyvinylpyrrolidone, as well as with sweeteners or tastecorrectors.

Rectal administration is effected using suppositories, which areprepared with binders melting at the rectal temperature, for examplecocoa butter or polyethylene glycols.

Parenteral, intranasal or intraocular administration is effected usingaqueous suspensions, isotonic saline solutions or injectable solutionswhich contain pharmacologically compatible dispersants and/or wettingagents, for example propylene glycol or butylene glycol.

Administration by inhalation is effected using an aerosol which alsocontains, for example, sorbitan trioleate or oleic acid, as well astrichlorofluoromethane, dichlorofluoromethane, dichlorotetrafluoroethaneor any other biologically compatible propellant gas; it is also possibleto use a system containing the active principle, by itself or inassociation with an excipient, in powder form.

The active principle can also be presented in the form of a complex witha cyclodextrin, for example α-, β- or γ-cyclodextrin,2-hydroxypropyl-β-cyclodextrin or methyl-β-cyclodextrin.

The active principle can also be formulated as microcapsules, with oneor more carriers or additives if appropriate.

In each dosage unit, the active principle of formula (I) is present inthe amounts commensurate with the daily doses envisaged. In general,each dosage unit is appropriately adjusted according to the dosage andthe intended type of administration, for example tablets, gelatincapsules and the like, sachets, ampoules, syrups and the like, or drops,so that said dosage unit contains from 0.5 to 1000 mg of activeprinciple, preferably from 2.5 to 250 mg, for administration one to fourtimes a day.

The above-mentioned compositions can also contain other active productswhich are useful for the desired therapeutics, such as, for example,bronchodilators, antitussives or antihistamines.

By virtue of their very high affinity for the human NK₃ receptor andtheir high selectivity, the compounds according to the invention may beused in radio-labeled form as laboratory reagents.

For example, they make it possible to characterize, identify and locatethe human NK₃ receptor in tissue sections or the NK₃ receptor in thewhole animal by autoradiography.

The compounds according to the invention also make it possible to sortor screen molecules as a function of their affinity for the human NK₃receptor. This is carried out by means of a reactionin which theradiolabeled ligand forming the subject of the present invention isdisplaced from its human NK₃ receptor.

The following abbreviations are used in the Preparations and in theExamples:

Me, OMe: methyl, methoxy

Et, OEt: ethyl, ethoxy

EtOH: ethanol

MeOH: methanol

Ether: diethyl ether

Iso ether: diisopropyl ether

DMF: dimethylformamide

DMSO: dimethyl sulfoxide

DCM: dichloromethane

THF: tetrahydrofiran

AcOEt: ethyl acetate

K₂ CO₃ : potassium carbonate

Na₂ CO₃ : sodium carbonate

KHCO₃ : potassium hydrogencarbonate

NaHCO₃ : sodium hydrogencarbonate

NaCl: sodium chloride

Na₂ SO₄ : sodium sulfate

MgSO₄ : magnesium sulfate

NaOH: sodium hydroxide

AcOH: acetic acid

H₂ SO₄ : sulfuric acid

HCl: hydrochloric acid

Ethereal hydrogen chloride: saturated solution of hydrochloric acid inether

BOP: benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate

KCN: potassium cyanide

DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene

NH₄ Cl: ammonium chloride

M.p.: melting point

B.p.: boiling point

RT: room temperature

Silica H: silica gel 60H marketed by Merck (DARMSTADT)

NMR: nuclear magnetic resonance

δ: chemical shift

s: singlet

bs: broad singlet

rs: resolved singlet

d: doublet

t: triplet

qd: quadruplet

sept: septuplet

mt: multiplet

us: unresolved signals

PREPARATION 1.1 4-(Pyrrolidin-1-ylcarbonyl)piperidine hydrochloride

A) 1-tert-Butoxycarbonyl-4-carboxypiperidine

8.6 g of triethylamine and 20 ml of water are added to a solution of 10g of isonipecotic acid in 100 ml of dioxane and the mixture is heated to60° C. 20.25 g of di-tert-butyl carbonate are then added dropwise andthe mixture is stirred for 1 hour at 60° C. and refluxed for 30 minutes.It is concentrated under vacuum, the residue is taken up with water andacidified to pH 3 by the addition of 2 N HCl solution and theprecipitate formed is filtered off to give 17 g of the expected product.

B) 1-tert-Butoxycarbonyl-4-(pyrrolidin-1-ylcarbonyl)piperidine

1.32 g of triethylamine, 2.5 g of the compound obtained in the previousstep and then 5.31 g of BOP are added to a solution of 0.77 g ofpyrrolidine in 20 ml of DCM and the mixture is stirred for 1 hour at RT.It is concentrated under vacuum, the residue is taken up with water andextracted with ether, the organic phase is washed with water, with 10%NaOH solution, with water, with a buffer solution of pH 2, with waterand with saturated NaCl solution and dried over MgSO₄ and the solvent isevaporated off under vacuum to give 2.25 g of the expected product

C) 4-(Pyrrolidin-1-ylcarbonyl)piperidine hydrochloride

20 ml of 6 N HCl solution are added to a solution of 2.25 g of thecompound obtained in the previous step in 40 ml of MeOH and the mixtureis stirred for 1 hour at RT. The solvent is concentrated under vacuum,the residue is taken up with acetone and the solvent is evaporated offunder vacuum to give 1.75 g of the expected product aftercrystallization from AcOEt.

PREPARATION 1.2 4-Carbamoyl-4-(piperid-1-yl)piperidine dihydrochloride

A) 1-Benzyl-4-cyano-4-(piperid-1-yl)piperidine

A solution of 5.3 g of sodium cyanide in 20 ml of water is addeddropwise at RT to a solution of 18.9 g of 1-benzylpiperid-4-one and12.16 g of piperidine hydrochloride in 25 ml of MeOH and 25 ml of waterand the mixture is stirred for 48 hours at RT. The precipitate formed isfiltered off, washed with water and dried under vacuum to give 27 g ofthe expected product.

B) 1-Benzyl-4-carbamoyl-4-(piperid-1-yl)piperidine

10 g of the compound obtained in the previous step are added to 50 ml of95% sulfuric acid and the mixture is heated at 100° C. for 45 minutes.After cooling to RT, the reaction mixture is poured onto 100 g of ice,250 ml of DCM are added, with cooling, the organic phase is dried overMgSO₄ and the solvent is evaporated off under vacuum. The solid productobtained is recrystallized from 300 ml of an acetonitrile/toluenemixture (65/35; v/v) to give 9.7 g of the expected product,m.p.=150-160° C.

C) 4-Carbamoyl-4-(piperid-1-yl)piperidine dihydrochloride

10 g of ammonium formate and 2.5 g of 5% palladium on charcoal are addedto a solution of 9.7 g of the compound obtained in the previous step in200 ml of MeOH and the mixture is stirred for 2 hours at RT. It isfiltered on Celite® and the filtrate is evaporated under vacuum. Theresidue is dissolved in 2 N HCl solution, rendered alkaline to pH 13 bythe addition of 40% NaOH solution and extracted with chloroform, theorganic phase is dried over MgSO₄ and the solvent is evaporated offunder vacuum. The product obtained is dissolved in an MeOH/DCM mixture,acidified to pH 1 by the addition of ethereal hydrogen chloride andevaporated under vacuum to give 5 g of the expected product, m.p.=185°C.

PREPARATION 1.3 4-(Acryloyl-N-methylamino)-4-phenylpiperidinehydrochloride

A) 1-Benzyl-4-hydroxy-4-phenylpiperidine

This compound is prepared by reacting phenyllithium with1-benzylpiperid-4-one by the method described in EP-A-474 561.

B) 4-Acetamido-1-benzyl-4-phenylpiperidine

This compound is prepared by reacting acetonitrile with the compoundobtained in the previous step by the method described in EP-A-474 561.

C) 4-Amino-1-benzyl-4-phenylpiperidine dihydrochloride

A mixture of 50 g of the compound obtained in the previous step, 90 mlof concentrated HCl solution and 210 ml of water is refluxed for 48hours. The reaction mixture is concentrated under vacuum, the residue istaken up with an EtOH/toluene mixture and the solvents are evaporatedoff under vacuum. The residue is dissolved in 100 ml of hot MeOH, 500 mlof acetone are added and the mixture is stirred, with cooling in an icebath. The crystals formed are filtered off, washed with acetone and thenwith ether and dried to give 48.9 g of the expected product.

D) 1-Benzyl-4-(formylamino)-4-phenylpiperidine

110 ml of acetic anhydride are added dropwise to a solution of 48.9 g ofthe compound obtained in the previous step and 25 g of sodium formate in340 ml of formic acid and the reaction mixture is then left to standovernight at RT, with stirring. It is concentrated under vacuum, theresidue is taken up with water, rendered alkaline by the addition ofconcentrated NaOH solution and extracted with DCM, the organic phase isdried over MgSO₄ and the solvent is evaporated off under vacuum to give38.8 g of the expected product after crystallization from an isoether/pentane mixture, m.p.=140° C.

E) 1-Benzyl-4-(methylamino)-4-phenylpiperidine

A solution of 38.8 g of the compound obtained in the previous step in400 ml of THF is added slowly to a suspension of 12.5 g of lithiumaluminum hydride in 100 ml of THF and the reaction mixture is refluxedfor 3 hours. After cooling, a solution of 5 ml of concentrated NaOH in45 ml of water is added, the inorganic salts are filtered off and thefiltrate is concentrated under vacuum to give 38 g of the expectedproduct.

F) 4-(Acryloyl-N-methylamino)- -benzyl-4-phenylpiperidine

A solution of 1.5 g of the compound obtained in the previous step and1.5 ml of triethylamine in 40 ml of DCM is cooled to 0-5° C., 0.5 ml ofacryloyl chloride is added dropwise and the reaction mixture is stirred,the temperature being allowed to rise to RT. It is poured into water,the resulting mixture is decanted, the organic phase is washed withwater and with 2 N NaOH solution and dried over MgSO₄ and the solvent isevaporated off under vacuum to give 1.3 g of the expected product aftercrystallization from an ether/pentane mixture.

G) 4-(Acryloyl-N-methylamino)-4-phenylpiperidine hydrochloride

A solution of 1.3 g of the compound obtained in the previous step in 30ml of 1,2-dichloroethane is cooled to 0° C., 0.5 ml of 1-chloroethylchloroformate is added dropwise and the reaction mixture is thenrefluxed for 2 hours. It is concentrated under vacuum and the residue istaken up with 15 ml of MeOH, refluxed for 30 minutes and concentratedunder vacuum to give 0.65 g of the expected product aftercrystallization from AcOEt.

PREPARATION 1.4 4-(2-Aminothiazol-4-yl)-4-phenylpiperidinep-toluenesulfonate monohydrate

A) 4-(2-Bromoacetyl)-4-phenylpiperidine hydrobromide

8 g of bromine are added rapidly at RT to a suspension of 11.98 g of4-acetyl-4-phenylpiperidine hydrochloride in 200 ml of DCM and thereaction mixture is left to stand overnight at RT, with stirring. It isdiluted by the addition of 200 ml of ether and the precipitate formed isfiltered off and washed with ether to give 17.88 g of the expectedproduct after drying under vacuum.

B) 4-(2-Aminothiazol-4-yl)-4-phenylpiperidine p-toluenesulfonatemonohydrate

A mixture of 7.26 g of the compound obtained in the previous step, 1.52g of thiourea and 150 ml of EtOH is refluxed for 3 hours. The reactionmixture is concentrated under vacuum, the residue is taken up with waterand rendered alkaline to pH 13 by the addition of 10% NaOH solution andthe precipitate formed is filtered off and washed with water and thenwith ether to give 4.46 g of the expected product in the form of thefree base after recrystallization from EtOH. 1 g of the base isdissolved in acetone and 0.73 g of p-toluenesulfonic acid mono-hydrateis added to give 1.5 g of the expected product in the form of crystals,m.p.=220-222° C.

PREPARATION 1.5 4-Acetyl-4-benzylpiperidine hydrochloride

A) 4-Cyanopiperidine

25 g of isonipecotamide (or piperidine-4-carboxamide) are added in smallportions to 70 ml of POCl₃ and the reaction mixture is refluxed for 4hours. It is concentrated under vacuum, the residue is taken up withice, rendered alkaline to pH 13 by the addition of concentrated NaOHsolution and extracted with DCM and then 4 times with ether, thecombined organic phases are dried over MgSO₄ and the solvents areevaporated off under vacuum. The oil obtained is distilled under reducedpressure to give 6.4 g of the expected product, b.p.=108-110° C. under18 mm of mercury.

B) 4-Cyano-1,4-dibenzylpiperidine

A solution of 15 g of the compound obtained in the previous step in 250ml of THF is cooled to -50° C., 190 ml of a 1.5 M solution of lithiumdiisopropylamide in cyclohexane are added dropwise and the mixture isstirred for 30 minutes at -50° C. 34 ml of benzyl bromide are then addedand the reaction mixture is stirred, the temperature being allowed torise to RT. After 3 hours at RT, it is poured into a mixture of ice andconcentrated HCl, ether is added and the precipitate formed is filteredoff and washed with water. The precipitate is taken up with water,rendered alkaline to pH 13 by the addition of concentrated NaOH solutionand extracted with ether, the organic phase is dried over MgSO₄ and thesolvent is evaporated off under vacuum to give 31.7 g of the expectedproduct after crystallization from pentane, m.p.=92° C.

C) 4-Acetyl-1,4-dibenzylpiperidine hydrochloride

55 ml of a 1.6 M solution of methyllithium in ether are added to asolution of 20 g of the compound obtained in the previous step in 400 mlof ether and the reaction mixture is stirred for 3 hours at RT. It ispoured into iced water, the resulting mixture is decanted, the organicphase is dried over MgSO₄ and the solvent is evaporated off undervacuum. The residue is taken up with 400 ml of water, 40 ml ofconcentrated HCl are added and the mixture is refluxed for 2 hours.After one night at RT, the crystalline product formed is filtered offand washed with a small amount of acetone and then with ether to give17.6 g of the expected product after drying, m.p.=246° C.

D) 4-Acetyl-4-benzylpiperidine hydrochloride

A mixture of 3 g of the compound obtained in the previous step, 0.3 g of10% palladium on charcoal, 50 ml of EtOH and 10 ml of water ishydrogenated at RT and at atmospheric pressure. The catalyst is filteredoff and the filtrate is evaporated under vacuum to give 1.8 g of theexpected product after crystallization from acetone, m.p.=195° C.

PREPARATION 1.6 4-(Acetylamino)-4-benzylpiperidine p-toluenesulfonate

A) 1,4-Dibenzyl-4-carboxypiperidine

6 g of the compound obtained in step B of PREPARATION 1.5 are added to asolution of 25 ml of water, 25 ml of concentrated H₂ SO₄ and 25 ml ofAcOH and the reaction mixture is heated at 140° C. for 5 hours. Aftercooling, it is poured onto ice, the pH is brought to 6.5 by the additionof concentrated NaOH solution and the mixture is stirred untilcrystallization takes place. The crystalline product is filtered off andwashed with water. The product is taken up with MeOH, filtered off andwashed with ether to give 3 g of the expected product, m.p.=262° C.

B) 1,4-Dibenzyl-4-isocyanatopiperidine

A mixture of 2 g of the compound obtained in the previous step and 1.6 gof phosphorus pentachloride in 40 ml of chloroform is heated at 60° C.for 1 hour. The reaction mixture is concentrated under vacuum, theresidue is taken up with 40 ml of acetone, a solution of 2 g of sodiumazide in 5 ml of water is added and the mixture is stirred for 30minutes at RT. It is concentrated under vacuum at RT, the residue istaken up with ether, the organic phase is washed with saturated Na₂ CO₃solution and with water and dried over MgSO₄ and the solvent isevaporated off under vacuum. The residue is taken up with 40 ml oftoluene and refluxed for 1 hour. It is concentrated under vacuum to give2 g of the expected product in the form of an oil.

C) 4-Amino-1,4-dibenzylpiperidine dihydrochloride

A mixture of 1 g of the compound obtained in the previous step and 20 mlof 8 N HCl is refluxed for 45 minutes. It is concentrated under vacuumand the residue is dissolved in the minimum amount of EtOH and pouredinto ether. The precipitate formed is filtered off, washed with etherand dried to give 1 g of the expected product, m.p.=199° C. (dec.).

D) 4-Acetylamino-1,4-dibenzylpiperidine

0.23 ml of acetyl chloride is added to a solution of 1 g of the compoundobtained in the previous step and 1.4 ml of triethylamine in 20 ml ofDCM and the reaction mixture is stirred for 15 minutes at RT. It iswashed with water and with saturated Na₂ SO₄ solution and dried overMgSO₄ and the solvent is evaporated off under vacuum to give 0.75 g ofthe expected product after crystallization from iso ether, m.p.=134° C.

E) 4-(Acetylamino)-4-benzylpiperidine p-toluenesulfonate

A mixture of 0.746 g of the compound obtained in the previous step, 0.44g of p-toluenesulfonic acid monohydrate, 0.2 g of 10% palladium oncharcoal and 30 ml of EtOH is stirred for 48 hours under a hydrogenatmosphere. The catalyst is filtered off and the filtrate isconcentrated under vacuum to give 0.88 g of the expected product in theform of a foam.

PREPARATION 1.7 4-Benzyl-4-cyanopiperidine

A) 4-Cyano-1-tritylpiperidine

A solution of 6.4 g of the compound obtained in step A of PREPARATION1.5 in 60 ml of DCM is cooled to 5° C., 10.8 ml of triethylamine areadded, 18 g of trityl chloride are then added slowly and the reactionmixture is stirred, the temperature being allowed to rise to RT. It iswashed with water and with a buffer solution of pH 2, the organic phaseis dried over MgSO₄ and the solvent is evaporated off under vacuum togive 19 g of the expected product after crystallization from iso ether,m.p.=206° C.

B) 4-Benzyl-4-cyano-1-tritylpiperidine

A solution of 5 g of the compound obtained in the previous step in 50 mlof THF is cooled to -50° C., 9.5 ml of a 1.5 M solution of lithiumdiisopropylamide in cyclohexane are added dropwise and the mixture isstirred for 30 minutes at -50° C. 1.7 ml of benzyl bromide are thenadded and the reaction mixture is stirred for 30 minutes. It is pouredinto a mixture of ice and a buffer solution of pH 2 and extracted withether, the extract is washed with saturated NaCl solution and dried overMgSO₄ and the solvent is evaporated off under vacuum to give 5.69 g ofthe expected product after crystallization from iso ether.

C) 4-Benzyl-4-cyanopiperidine

A mixture of 5.7 g of the compound obtained in the previous step, 25 mlof formic acid and 25 ml of water is heated at 60° C. for 1 hour. Aftercooling to RT, the insoluble material is filtered off and washed withwater and the filtrate is evaporated under vacuum. The residue is takenup with water, rendered alkaline to pH 13 by the addition ofconcentrated NaOH solution and extracted with ether, the organic phaseis dried over MgSO₄ and the solvent is evaporated off under vacuum togive 2.5 g of the expected product.

PREPARATION 1.8 4-Benzyl-4-(ethoxycarbonylamino)piperidinep-toluenesulfonate

A) 1,4-Dibenzyl-4-(ethoxycarbonylamino)piperidinep-toluenesulfonate

A mixture of 1 g of the compound obtained in step B of PREPARATION 1.6and 20 ml of EtOH is refluxed for 24 hours. It is concentrated undervacuum, the oil obtained is dissolved in 5 ml of acetone, 0.55 g ofpara-toluenesulfonic acid monohydrate is added and ether is then addeduntil crystallization takes place. The crystals formed are filtered off,washed with ether and dried to give 1.38 g of the expected product,m.p.=154° C.

B) 4-Benzyl-4-(ethoxycarbonylamino)piperidinep-toluenesulfonate

A mixture of 1.3 g of the compound obtained in the previous step, 0.15 gof 10% palladium on charcoal and 20 ml of EtOH is stirred for 24 hoursunder a hydrogen atmosphere. The catalyst is filtered off and thefiltrate is concentrated under vacuum to give 1 g of the expectedproduct in the form of a foam.

PREPARATION 1.9 4-Benzyl-4-(pyrrolidin-1-ylcarbonyl)piperidinep-toluenesulfonate

A) 1,4-Dibenzyl-4-(pyrrolidin-1-ylcarbonyl)piperidine

0.5 g of pyrrolidine and then 3.8 g of BOP are added to a solution of2.2 g of the compound obtained in step A of PREPARATION 1.6 and 2.5 mlof triethylamine in 50 ml of DCM and the reaction mixture is stirred for1 hour at RT. It is concentrated under vacuum, the residue is extractedwith AcOEt, the organic phase is washed with water, with 1 N NaOHsolution, with water and with saturated NaCl solution and dried overMgSO₄ and the solvent is evaporated off under vacuum. The residue ischromatographed on silica using DCM and then a DCM/MeOH mixture (90/10;v/v) as the eluent. The product obtained is taken up with an ether/1 NHCl mixture, the resulting mixture is decanted, the aqueous phase isrendered alkaline to pH 13 by the addition of 1 N NaOH and extractedwith DCM, the organic phase is dried over MgSO₄ and the solvent isevaporated off under vacuum to give 0.64 g of the expected product aftercrystallization from iso ether, m.p.=129° C.

B) 4-Benzyl-4-(pyrrolidin-1-ylcarbonyl)piperidine p-toluenesulfonate

A mixture of 0.64 g of the compound obtained in the previous step, 0.33g of p-toluenesulfonic acid monohydrate, 0.1 g of 10% palladium oncharcoal and 10 ml of EtOH is hydrogenated at RT and at atmosphericpressure. The catalyst is filtered off and the filtrate is evaporatedunder vacuum to give 0.75 g of the expected product in the form of afoam.

PREPARATION 1.10 4-(Acetyl-N-methylamino)-4-phenylpiperidinep-toluenesulfonate

A) 4-(Acetyl-N-methylamino)-1-benzyl-4-phenylpiperidine

A solution of 30 g of the compound obtained in step E of PREPARATION 1.3and 16.5 ml of triethylamine in 300 ml of DCM is cooled to 0-5° C., 8 mlof acetyl chloride are added dropwise and the reaction mixture isstirred for 30 minutes at RT. It is washed twice with water and with 2 NNaOH solution, the organic phase is dried over MgSO₄ and the solvent isevaporated off under vacuum to give 31.6 g of the expected product aftercrystallization from an iso ether/pentane mixture, m.p.=104° C.

B) 4-(Acetyl-N-methylamino)-4-phenylpiperidine p-toluenesulfonate

A mixture of 5 g of the compound obtained in the previous step, 2.9 g ofp-toluenesulfonic acid monohydrate, 0.5 g of 10% palladium on charcoaland 80 ml of EtOH is hydrogenated for 3 hours at 25° C. and atatmospheric pressure. The catalyst is filtered off and the filtrate isconcentrated under vacuum to give 5.7 g of the expected product aftercrystallization from acetone, m.p.=165° C.

PREPARATION 1.11 4-Phenyl-4-(pyrrolidin-1-ylcarbonyl)piperidinehemihydrate

A) 1-tert-Butoxycarbonyl-4-carboxy-4-phenylpiperidine

30 ml of water and 32.9 g of K₂ CO₃ are added to a mixture of 30 g of4-carboxy-4-phenylpiperidine p-toluenesulfonate and 300 ml of dioxane,the resulting mixture is then heated to 60° C. and 18.2 g ofdi-tert-butyl dicarbonate are added dropwise. The reaction mixture issubsequently heated for 2 hours at 60° C. and then for 30 minutes underreflux. After cooling to RT, it is concentrated under vacuum, theresidue is extracted with DCM, the organic phase is washed with a buffersolutiori of pH 2, acidified to pH 4 by the addition of 2 N HCl, washedwith a buffer solution of pH 2, with water and with saturated NaClsolution and dried over MgSO₄ and the solvent is evaporated off undervacuum to give 23.7 g of the expected product.

B) 1-tert-Butoxycarbonyl-4-(pyrrolidin-1-ylcarbonyl)-4-phenylpiperidine

9.29 g of triethylamine and then 3.27 g of pyrrolidine are added to asolution of 14 g of the compound obtained in the previous step in 200 mlof DCM. The mixture is cooled in an ice bath, 22.4 g of BOP are addedand the reaction mixture is stirred, the temperature being allowed torise to RT. It is concentrated under vacuum, the residue is extractedwith DCM, the organic phase is washed with water, three times with 10%NaOH solution, with water, three times with a buffer solution of pH 2,with water and with saturated NaCl solution and dried over MgSO₄ and thesolvent is evaporated off under vacuum to give 16.4 g of the expectedproduct.

C) 4-Phenyl-4-(pyrrolidin-1-ylcarbonyl)piperidine hemihydrate

Concentrated HCl solution is added to a solution of 16.4 g of thecompound obtained in the previous step in 200 ml of MeOH until the pH is1, and the reaction mixture is stirred for 5 hours at RT. It isconcentrated under vacuum, the residue is taken up with acetone and thesolvent is evaporated off under vacuum to give a white solid, which isrecrystallized from propan-2-ol. The product obtained is taken up with10% NaOH solution and extracted with DCM, the organic phase is washedwith 10% NaOH solution and with saturated NaCl solution and dried overMgSO₄ and the solvent is evaporated off under vacuum to give 7 g of theexpected product after crystallization from ether, m.p.=126° C.

PREPARATION 1.12 4-(N,N-Dimethylaminocarbonyl)-4-phenylpiperidine

A)1-tert-Butoxycarbonyl-4-(N,N-dimethylaminocarbonyl)-4-phenylpiperidine

8.1 g of triethylamine and then 4.9 g of dimethylamine hydrochloride areadded to a solution of 6.11 g of the compound obtained in step A ofPREPARATION 1.11 in 20 ml of DCM and 20 ml of DMF. The mixture is cooledin an ice bath, 9.73 g of BOP are added and the resulting mixture isstirred for 3 hours, the temperature being allowed to rise to RT. It isconcentrated under vacuum, the residue is extracted with ether, theorganic phase is washed with water, with a buffer solution of pH 2, with10% NaOH solution, with water and with saturated NaCl solution and driedover MgSO₄ and the solvent is evaporated off under vacuum to give 6.45 gof the expected product.

B) 4-(N,N-Dimethylaminocarbonyl)-4-phenylpiperidine

Concentrated HCl solution is added to a solution of 6.4 g of thecompound obtained in the previous step in 80 ml of MeOH until the pH is1, and the mixture is stirred for 4 hours at RT. It is concentratedunder vacuum, the residue is extracted with DCM, the organic phase iswashed three times with 10% NaOH solution and with saturated NaClsolution and dried over MgSO₄ and the solvent is evaporated off undervacuum to give 3.2 g of the expected product after crystallization fromether, m.p.=95° C.

PREPARATION 1.13 4-(2-Hydroxyethoxy)-4-phenylpiperidine hydrochloride

A) 1-Benzyl-4-hydroxy-4-phenylpiperidine

This compound is prepared by reacting phenyllithium with1-benzylpiperid-4-one by the method described in EP-A-474 561.

B) 4-(Benzoyloxy)-1-benzyl-4-phenylpiperidine

A solution of 2.67 g of the compound prepared in the previous step and2.5 ml of triethylamine in 30 ml of DCM is cooled to 0-5° C., 1.22 ml ofbenzoyl chloride are added and the reaction mixture is stirred for 1hour, the temperature being allowed to rise to RT. It is concentratedunder vacuum, the residue is extracted with AcOEt, the organic phase iswashed with water and with 1 N NaOH solution and dried over MgSO₄ andthe solvent is evaporated off under vacuum to give 2.4 g of the expectedproduct after crystallization from pentane.

C) 1-Benzyl-4-(2-hydroxyethoxy)-4-phenylpiperidine hydrochloride

A mixture of 2.3 g of the compound obtained in the previous step, 7 mlof H₂ SO₄ and 60 ml of ethylene glycol is heated at 60° C. for 5 hours.The reaction mixture is poured onto ice, rendered alkaline by theaddition of concentrated NH₄ OH solution and extracted with DCM, theorganic phase is washed with water and dried over MgSO₄ and the solventis evaporated off under vacuum. The residue is chromatographed on silicausing DCM and then a DCM/MeOH mixture (96/4; v/v) as the eluent. Theproduct obtained is dissolved in DCM and acidified to pH 1 by theaddition of ethereal hydrogen chloride and the precipitate formed isfiltered off to give 1 g of the expected product.

D) 4-(2-Hydroxyethoxy)-4-phenylpiperidine hydrochloride

A mixture of 3.3 g of the compound obtained in the previous step, 0.4 gof 10% palladium on charcoal and 100 ml of EtOH is hydrogenated at RTand at atmospheric pressure. The catalyst is filtered off on Celite® andthe filtrate is concentrated under vacuum to give 2.2 g of the expectedproduct, m.p.=168-172° C.

PREPARATION 1.14 4-Amino-4-phenylpiperidine dibenzenesulfonate

26.95 g of the compound obtained in step C of PREPARATION 1.3 aredissolved in 50 ml of water, rendered alkaline to pH 12 by the additionof concentrated NaOH solution and extracted with DCM, the organic phaseis washed with saturated NaCl solution and dried over Na₂ SO₄ and thesolvent is evaporated off under vacuum. The oil obtained is taken upwith 300 ml of EtOH, 25 g of benzenesulfonic acid and 2.2 g of 5%palladium on charcoal are added and the mixture is then hydrogenated at40° C. and at atmospheric pressure. The catalyst is filtered off onCelite and washed with MeOH and the filtrate is concentrated undervacuum. The residue is taken up with acetone and the precipitate formedis filtered off to give 29.7 g of the expected product, m.p.=276-278° C.

PREPARATION 1.15 4-(2-Amino-1,3,4-oxadiazol-5-yl)-4-phenylpiperidinep-toluenesulfonate

A) 1-(Benzyloxycarbonyl)-4-carboxy-4-phenylpiperidine

A mixture of 37.7 g of 4-carboxy-4-phenylpiperidine p-toluenesulfonate,53.3 g of 30% aqueous NaOH solution and 250 ml of water is cooled to 5°C. A solution of 18 g of benzyl chloroformate in 60 ml of acetone isadded rapidly at 5° C. and the reaction mixture is stirred overnight,the temperature being allowed to rise to RT. It is washed twice withether and, after decantation, the aqueous phase is acidified to pH 1 bythe addition of concentrated HCl and then 2 N HCl. The precipitateformed is filtered off, dried, taken up with ether and filtered offagain to give 30.6 g of the expected product, m.p.=142-144° C.

B) 1-(Benzyloxycarbonyl)-4-(chloroformyl)-4-phenylpiperidine

A mixture of 17.1 g of the compound obtained in the previous step, 24 gof thionyl chloride and 150 ml of 1,2-dichloroethane is refluxed for 1hour. It is concentrated under vacuum, the residue is taken up withchloroform and the solvent is evaporated off under vacuum. The residueis taken up with an ether/pentane mixture and the solvents areevaporated off again under vacuum to give 20 g of the expected productin the form of a gum, which is used as such.

C) 1-(Benzyloxycarbonyl)-4-carbazoyl-4-phenylpiperidine

A solution of 16 g of hydrazine monohydrate in 40 ml of EtOH is cooledto -50° C., a solution of 11.44 g of the compound obtained in theprevious step in 20 ml of 1,2-dimethoxyethane is added dropwise and themixture is stirred, the temperature being allowed to rise to RT. It isconcentrated under vacuum, the residue is taken up with water andextracted with DCM, the organic phase is washed with water and withsaturated NaCl solution and dried over MgSO₄ and the solvent isevaporated off under vacuum. The residue is taken up with anEtOH/benzene mixture and the solvents are evaporated off under vacuum togive 11.2 g of the expected product in the form of a gum, which is usedas such.

D)4-(2-Amino-1,3,4-oxadiazol-5-yl)-1-(benzyloxycarbonyl)-4-phenylpiperidine

A solution of 3.39 g of cyanogen bromide in 10 ml of EtOH is added at RTto a solution of 11.2 g of the compound obtained in the previous step in60 ml of EtOH and the reaction mixture is refluxed for 1 hour. It isconcentrated to 50 ml of EtOH and water is then added dropwise until thevolume of the reaction mixture is 400 ml. The crystalline product formedis filtered off, washed with water, then with DCM, with AcOEt and withether to give 8 g of the expected product

E) 4-(2-Amino-1 ,3,4-oxadiazol-5-yl)-4-phenylpiperidinep-toluenesulfonate

A mixture of 7.85 g of the compound obtained in the previous step, 3.95g of p-toluenesulfonic acid monohydrate, 0.8 g of 10% palladium oncharcoal, 350 ml of 95° EtOH and 10 ml of water is hydrogenated at 50°C. and at atmospheric pressure. After 3 hours, the catalyst is filteredoff on Celite® and the filtrate is concentrated under vacuum. Theresidue is taken up with acetone and the crystalline product formed isfiltered off and washed with acetone and then with ether to give 7.65 gof the expected product, m.p.=183-185° C.

PREPARATION 1.16 4-Carbamoyl-4-(morpholin-4-yl)piperidine

A) 1-Benzyl-4-cyano-4-(morpholin4-yl)piperidine

2.5 ml of morpholine and then 5.1 g of Na₂ S₂ O₅ are added to a mixtureof 5 g of 1-benzylpiperid4-one and 1.9 g of potassium cyanide in 50 mlof an EtOH/water mixture (50/50; v/v) and the resulting mixture isheated at 60° C. for 2 hours. A further 2.5 ml of morpholine are addedand the reaction mixture is stirred overnight at RT. Water is added andthe crystalline product formed is filtered off to give 5.5 g of theexpected product.

B) 1-Benzyl-4-carbamoyl-4-(morpholin4-yl)piperidine

A mixture of 14 g of the compound obtained in the previous step and 50ml of 95% sulfuric acid is heated at 100° C. for 2 hours. After coolingto RT, the reaction mixture is poured onto 100 g of ice, the pH isbrought to 7 by the addition of concentrated NH₄ OH solution, themixture is extracted with DCM, the organic phase is washed with waterand dried over Na₂ SO₄ and the solvent is evaporated off under vacuum.The residue is chromatographed on silica H using a DCM/MeOH mixture(100/5; v/v to 100/10; v/v) as the eluent to give 3.4 g of the expectedproduct after crystallization from iso ether.

C) 4-Carbamoyl-4-(morpholin-4-yl)piperidine

3.1 g of ammonium formate and 0.8 g of 5% palladium on charcoal areadded to a solution of 3.4 g of the compound obtained in the previousstep in 50 ml of MeOH and the mixture is stirred for 2 hours at RT. Thecatalyst is filtered off on Celite® and the filtrate is evaporated undervacuum to give 2.2 g of the expected product after crystallization frompropan-2-ol.

PREPARATIONS 1.17 to 1.21

The following are obtained by carrying out the procedure described inPREPARATION 1.16 and replacing the morpholine in step A withthiomorpholine, azetidine, pyrrolidine, perhydroazepine,di-n-heptylamine and di-n-butylamine:

4-carbamoyl-4-(thiomorpholin-4-yl)piperidine (1.17);

4-carbamoyl-4-(azetidin-1-yl)piperidine (1.18);

4-carbamoyl-4-(perhydroazepin-1-yl)piperidine (1.19);

4-carbamoyl-4-(di-n-heptylamino)piperidine (1.20);

4-carbamoyl-4-(di-n-butylamino)piperidine (1.21).

PREPARATIONS 1.22 to 1.26

The following are obtained by carrying out the procedure described inPREPARATION 1.9, starting from the 1,4-dibenzyl-4-carboxypiperidineobtained in step A of PREPARATION 1.6 and replacing the pyrrolidine withazetidine, piperidine, morpholine, perhydroazepine and1-methylpiperazine:

4-benzyl-4-(azetidin-1-ylcarbonyl)piperidine p-toluenesulfonate (1.22);

4-benzyl-4-(piperidin-1-ylcarbonyl)piperidine p-toluenesulfonate (1.23);

4-benzyl-4-(morpholin-4-ylcarbonyl)piperidine p-toluenesulfonate (1.24);

4-benzyl-4-(perhydroazepin-1-ylcarbonyl)piperidine p-toluenesulfonate(1.25);

4-benzyl-4-(4-methylpiperazin-1-ylcarbonyl)piperidine p-toluenesulfonate(1.26).

PREPARATIONS 1.27 to 1.31

The following are obtained by carrying out the procedure described inPREPARATION 1.11, steps B and C, and replacing the pyrrolidine in step Bwith azetidine, piperidine, morpholine, perhydroazepine and1-methylpiperazine:

4-(azetidin-1-ylcarbonyl)-4-phenylpiperidine (1.27);

4-(piperidin-1-ylcarbonyl)-4-phenylpiperidine (1.28);

4-(morpholin-4-ylcarbonyl)-4-phenylpiperidine (1.29);

4-(perhydroazepin-1-ylcarbonyl)-4-phenylpiperidine (1.30);

4-(4-methylpiperazin-1-ylcarbonyl)-4-phenylpiperidine (1.31).

PREPARATION 1.32 4-(N-Methylcarbamoyl)-4-phenylpiperidine

A) 1-tert-Butoxycarbonyl-4-(N-methylcarbamoyl)-4-phenylpiperidine

1.98 g of triethylamine and then 0.49 g of methylamine hydrochloride areadded to a solution of 1.5 g of the compound obtained in step A ofPREPARATION 1.11 in 5 ml of DCM and 5 ml of DMF. The mixture is cooledin an ice bath, 2.39 g of BOP are added and the reaction mixture isstirred for 24 hours, the temperature being allowed to rise to RT. It isconcentrated under vacuum and the residue is extracted with ether,washed with water and with saturated NaCl solution, dried over MgSO₄ andevaporated under vacuum to give 1.4 g of the expected product.

B) 4-(N-Methylcarbamoyl)-4-phenylpiperidine

4 ml of concentrated HCl are added to a solution of 1.4 g of thecompound obtained in the previous step in 30 ml of MeOH and the mixtureis stirred for 1 hour at RT. It is concentrated under vacuum, theresidue is extracted with DCM, washed with water and twice with 10% NaOHsolution and dried over MgSO₄ and the solvent is evaporated off undervacuum to give 0.6 g of the expected product.

PREPARATION 1.33 4-(N-n-Butylcarbamoyl)-4-phenylpiperidine

A) 1-tert-Butoxycarbonyl-4-(N-n-butylcarbamoyl)-4-phenylpiperidine

This compound is prepared by the procedure described in step A ofPREPARATION 1.32, starting from 1.0 g of the compound obtained in step Aof PREPARATION 1.11 and 0.24 g of n-butylamine. This gives 1.3 g of theexpected product, which is used as such in the next step.

B) 4-(N-n-Butylcarbamoyl)-4-phenylpiperidine

This compound is prepared by the procedure described in step B ofPREPARATION 1.32. This gives 0.4 g of the expected product.

PREPARATION 1.34 4-(N,N-Diethylcarbamoyl)-4-phenylpiperidinetrifluoroacetate

A) 1-tert-Butoxycarbonyl-4-(N,N-diethylcarbamoyl)-4-phenylpiperidine

This compound is prepared by the procedure described in step A ofPREPARATION 1.32, starting from 1.5 g of the compound obtained in step Aof PREPARATION 1.11 and 0.8 g of diethylamine hydrochloride. This gives1.7 g of the expected product.

B) 4-(N,N-Diethylcarbamoyl)-4-phenylpiperidine trifluoroacetate

1.7 g of the compound obtained in the previous step are dissolved in 20ml of trifluoroacetic acid and the solution is stirred at RT for 30minutes. It is concentrated under vacuum, the residue is taken up withether and the mixture is evaporated under vacuum to give 2.8 g of theexpected product in the form of an oil.

PREPARATION 1.35 4-Carbamoyl-4-phenylpiperidine

A) 1-tert-Butoxycarbonyl-4-carbamoyl-4-phenylpiperidine

A solution of 1.5 g of the compound obtained in step A of PREPARATION1.11, 0.99 g of triethylamine and 2.39 g of BOP in 10 ml of DCM iscooled to -20° C. and ammonia gas is then bubbled into the solution. Thetemperature is allowed to rise to RT and the reaction mixture is stirredfor 2 hours. It is concentrated under vacuum, the residue is extractedwith ether, the organic phase is washed with water, with a buffersolution of pH 2, with water, with 10% NaOH solution, with water andwith saturated NaCl solution and dried over MgSO₄ and the solvent isevaporated off under vacuum to give 1.32 g of the expected product

B) 4-Carbamoyl-4-phenylpiperidine

This compound is prepared by the procedure described in step B ofPREPARATION 1.32, starting from 1.32 g of the compound obtained in theprevious step. This gives 0.41 g of the expected product.

PREPARATION 1.36 4-(N-Isopropylcarbamoyl)-4-phenylpiperidine

A) 1-tert-Butoxycarbonyl-4-(N-isopropylcarbamoyl)-4-phenylpiperidine

This compound is prepared by the procedure described in step A ofPREPARATION 1.32, starting from 1.5 g of the compound obtained in step Aof PREPARATION 1.11 and 0.29 g of isopropylamine. This gives 1.61 g ofthe expected product.

B) 4-(N-Isopropylcarbamoyl)-4-phenylpiperidine

This compound is prepared by the procedure described in step B ofPREPARATION 1.32, starting from 1.61 g of the compound obtained in theprevious step. This gives 1.1 g of the expected product.

PREPARATION 2.1 3-(3,4-Dichlorophenyl)-3-(3-hydroxypropyl)piperidinehydrochloride

A) Methyl 4-cyano-4-(3,4-dichlorophenyl)heptanedioate

In a three-necked flask, 37.2 g of 3,4-dichlorophenylacetonitrile and34.43 g of methyl acrylate are dissolved in 20 ml of dioxane; 1 ml ofDBU is added and the mixture is heated for 2 hours at 60° C.,evaporated, diluted with 400 ml of ethyl acetate, then washed withdilute HCl and NaCl solution, dried over MgSO₄ and evaporated. Theexpected product is crystallized from 100 ml of ethyl acetate and 100 mlof ether with 100 ml of heptane to give 47 g of product

B) Methyl 3-[5-(3,4-dichlorophenyl)-2-oxopiperid-5-yl]propionate

40 g of the compound prepared in step A are dissolved in 500 ml of2-methoxyethanol, 2 g of Raney nickel are added and the mixture ishydrogenated at 40° C. under atmospheric pressure for 3 days. It isfiltered and evaporated to give the expected product in the form of anoil (39 g).

C) 3-[5-(3,4-Dichlorophenyl)-2-oxopiperid-5-yl]propanoic acid

17 g of the compound prepared in the previous step are dissolved in 250ml of methanol, 2.8 g of potassium hydroxide and 10 ml of water areadded and the mixture is then refluxed for 2 hours. It is evaporated todryness and the oil obtained is taken up with 200 ml of water and washedwith 100 ml of ethyl acetate. The aqueous phase is acidified with 30%HCl solution and the precipitate formed is then filtered off and dried.It is recrystallized from hot methanol to give 18.3 g of the expectedcompound.

D) 3-(3,4-Dichlorophenyl)-3-(3-hydroxypropyl)piperidine hydrochloride

5 g of the compound obtained in the previous step are dissolved in 20 mlof THF, 75 ml of borane (concentration: 1 M in THF) are added and themixture is refluxed for 24 hours under nitrogen. 25 ml of methanol and50 ml of 4 N HCl are added, the mixture is stirred for 30 minutes and40% sodium hydroxide is then added until the pH exceeds 10. The mixtureis extracted 3 times with 150 ml of DCM and the organic phase is driedover MgSO₄ and evaporated. The residue is dissolved in DCM with a 4 Nsolution of HCl in ether. After evaporation, a foam is obtained and theexpected product (4.5 g) crystallizes from an AcOEt/ether mixture.

PREPARATION 2.23-(3,4-Dichlorophenyl)-3-[3-(tetrahydropyran-2-yloxy)propyl]perhydroazepine

A) Ethyl 5-cyano-5-(3,4-dichlorophenyl)pentanoate

11.8 g of a 55% dispersion of sodium hydride in oil are suspended in 100ml of THF and cooled in an ice bath, a solution of 50 g of3,4-dichlorophenylacetonitrile in 50 ml of THF is added dropwise and thereaction mixture is stirred for 3 hours at RT. It is cooled again in anice bath, a solution of 52.4 g of ethyl 4-bromobutanoate in 50 ml of THFis added dropwise and the mixture is stirred overnight at RT. It isconcentrated under vacuum, the residue is taken up with water andextracted with ether, the organic phase is washed with water, with abuffer solution of pH 2, with water and with saturated NaCl solution anddried over MgSO₄ and the solvent is evaporated off under vacuum. Theresidue is chromatographed on silica using toluene and then atoluene/AcOEt mixture (100/5; v/v) as the eluent to give 36.9 g of theexpected product.

B) Ethyl5-cyano-5-(3,4-dichlorophenyl)-8-(tetrahydropyran-2-yloxy)octanoate

5 g of a 55% dispersion of sodium hydride in oil are suspended in 100 mlof DMF and cooled to -20° C., a solution of 25.4 g of2-(3-bromopropoxy)tetrahydropyran and 34.2 g of the compound obtained inthe previous step in 100 ml of DMF is added dropwise and the reactionmixture is stirred overnight at RT. It is concentrated under vacuum, theresidue is taken up with a mixture of water and a buffer solution of pH4 and extracted with AcOEt, the organic phase is washed with a buffersolution of pH 4, with water and with saturated NaCl solution and driedover MgSO₄ and the solvent is evaporated off under vacuum. The residueis chromatographed on silica using toluene and then a toluene/AcOEtmixture (100/10; v/v) as the eluent to give 36 g of the expectedproduct.

C) Ethyl5-(aminomethyl)-5-(3,4-dichlorophenyl)-8-(tetrahydropyran-2-yloxy)-octanoate

30 ml of a saturated solution of ammonia in MeOH and 2 g of Raney®nickel are added to a solution of 16.7 g of the compound obtained in theprevious step in 200 ml of MeOH and the mixture is then hydrogenated at40° C. and at atmospheric pressure. The catalyst is filtered off onCelite® and the filtrate is concentrated under vacuum. The residue isextracted with ether, the organic phase is washed with water and withsaturated NaCl solution and dried over MgSO₄ and the solvent isevaporated off under vacuum to give 15.1 g of the expected product.

D)6-(3,4-Dichlorophenyl)-6-[3-(tetrahydropyran-2-yloxy)propyl]perhydroazepin-2-one

A solution of 15.1 g of the compound obtained in the previous step in150 ml of xylene is refluxed for 48 hours. After cooling to RT, thereaction mixture is concentrated under vacuum to give 13.5 g of theexpected product.

E)3-(3,4-Dichlorophenyl)-3-[3-tetrahydropyran-2-yloxy)propyl]perhydroazepine

A solution of 14 g of the compound obtained in the previous step in 200ml of THF is added dropwise to a suspension of 4 g of lithium aluminumhydride in 100 ml of THF and the mixture is then refluxed for 2 hours.After cooling to RT, 4 ml of water, 12 ml of 10% NaOH solution and 4 mlof water are added in succession. The inorganic salts are filtered offon Celite® and the filtrate is concentrated under vacuum. The residue isextracted with DCM, the organic phase is dried over MgSO₄ and thesolvent is evaporated off under vacuum to give 13 g of the expectedproduct.

EXAMPLE 11-Benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]piperidinehydrochloride 1.5 hydrate

A) 1-Benzoyl-3-(3,4-dichlorophenyl)-3-(3-hydroxypropyl)piperidine

A solution of 16.22 g of the compound obtained in PREPARATION 2.1 and18.2 g of triethylamine in 250 ml of DCM is cooled in an ice bath and asolution of 14.06 g of benzoyl chloride in 10 ml of DCM is addeddropwise. The mixture is stirred for 1 hour, the temperature beingallowed to rise to RT. The excess benzoyl chloride is removed by theaddition of MeOH and the reaction mixture is then concentrated undervacuum. The residue is taken up with MeOH and the solvent is evaporatedoff under vacuum. The residue is extracted with ether, washed withwater, with 2 N HCl solution, with 5% NaHCO₃ solution and with saturatedNaCl solution, dried over MgSO₄ and evaporated under vacuum. The1-benzoyl-3-(3,4-dichlorophenyl)-3-(3-benzoyloxypropyl)piperidine thusobtained as an intermediate is dissolved in 150 ml of MeOH, 10% NaOHsolution is added and the mixture is heated for 1 hour at 50-60° C. andconcentrated under vacuum. The residue is extracted with ether, washedwith water, with 2 N HCl solution, with 5% NaHCO₃ solution and withsaturated NaCl solution and dried over MgSO₄ and the solvent isevaporated off under vacuum to give 18 g of the expected product in theform of an oil.

B)1-Benzoyl-3-(3,4-dichlorophenyl)-3-[3-(methanesulfonyloxy)propyl]piperidine

A solution of 16.8 g of the compound obtained in the previous step and5.18 g of triethylamine in 100 ml of DCM is cooled in an ice bath, asolution of 5.40 g of methanesulfonyl chloride in 10 ml of DCM is addeddropwise and the mixture is then stirred for 30 minutes, the temperaturebeing allowed to rise to RT. It is concentrated under vacuum, theresidue is extracted with AcOEt, washed with water, with 2 N HClsolution and with saturated NaCl solution and dried over MgSO₄ and thesolvent is evaporated off under vacuum to give 19.6 g of the expectedproduct in the form of an oil.

Proton NMR spectrum at 200 MHz in DMSO-d₆

1 to 2.35 ppm: us: 8H

3.15 ppm: s: 3H

3.2 to 4.6 ppm: us: 6H

6.8 to 7.8ppm: us: 8H

C)1-Benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]piperidinehydrochloride 1.5 hydrate

0.56 g of 4-(pyrrolidin-1-ylcarbonyl)piperidine hydrochloride isdissolved in water, the solution is rendered alkaline by the addition of10% NaOH solution and extracted with DCM, the organic phase is washedwith saturated NaCl solution and dried over MgSO₄ and the solvent isevaporated off under vacuum. The residue is taken up with 5 ml of DMFand 5 ml of acetonitrile, 1 g of the compound obtained in the previousstep and then 0.88 g of K₂ CO₃ are added and the reaction mixture isheated at 100° C. for 4 hours. It is concentrated under vacuum, theresidue is taken up with water and extracted with AcOEt, the organicphase is washed with water and with saturated NaCl solution and driedover MgSO₄ and the solvent is evaporated off under vacuum. The residueis chromatographed on silica H using DCM and then a DCM/MeOH mixture(95/5; v/v) as the eluent. The product obtained is taken up with AcOEtand acidified by the addition of ethereal hydrogen chloride and theprecipitate formed is filtered off to give 0.8 g of the expectedproduct, m.p.=146° C.

EXAMPLE 21-Benzoyl-3-(3,4-dichlorophenyl)-3-[3-(4-piperidinopiperid-1-yl)propyl]-piperidinedihydrochloride hemihydrate

A mixture of 0.55 g of 4-piperidinopiperidine, 1.3 g of the compoundobtained in step B of EXAMPLE 1 and 1.14 g of K₂ CO₃ in 10 ml of aDMF/acetonitrile mixture (50/50; v/v) is heated at 100° C. for 3 hours.The reaction mixture is poured into water and extracted with AcOEt, theorganic phase is washed twice with water and with saturated NaClsolution and dried over MgSO₄ and the solvent is evaporated off undervacuum. The residue is chromatographed on silica H using DCM and then aDCM/MeOH mixture (98/2; v/v) as the eluent. The product obtained isdissolved in AcOEt, a stream of HCl gas is bubbled into the solutionuntil the pH is 1, and ether is added until precipitation occurs. Thisgives 0.53 g of the expected product after filtration and drying,m.p.=265° C. (dec.).

EXAMPLE 31-Benzoyl-3-(3,4-dichlorophenyl)-[3-[4-carbamoyl-4-(piperid-1-yl)piperid-1-yl]propyl]piperidinedihydrochloride 1.5 hydrate

2.6 g of 4-carbamoyl-4-(piperid-1-yl)piperidine dihydrochloride aredissolved in water, the solution is rendered alkaline by the addition ofconcentrated NaOH solution and extracted with DCM, the extract is driedover MgSO₄ and the solvent is evaporated off under vacuum. The residueis taken up with 10 ml of acetonitrile, 1.55 g of the compound obtainedin step B of EXAMPLE 1 are added and the reaction mixture is refluxedfor 2 hours. It is concentrated under vacuum, the residue is extractedwith AcOEt, the organic phase is washed with water, with 1 N NaOHsolution and with saturated NaCi solution and dried over MgSO₄ and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica H using a gradient of a DCM/MeOH mixture (99/1; v/v to 93/7;v/v) as the eluent. The product obtained is taken up with DCM andacidified by the addition of ethereal hydrogen chloride and the mixtureis evaporated under vacuum to give 2 g of the expected product,m.p.=210° C.

EXAMPLE 43-[3-[4-(Acryloyl-N-methylamino)-4-phenylpiperid-1-yl]propyl]-1-benzoyl-3-(3,4-dichlorophenyl)piperidinehydrochloride

A mixture of 0.27 g of 4-(acryloyl-N-methylamino)-4-phenylpiperidinehydrochloride, 0.45 g of the compound obtained in step B of EXAMPLE 1and 0.3 g of K₂ CO₃ in 3 ml of DMF is heated at 80° C. for 2 hours. Thereaction mixture is poured into water and extracted with AcOEt, theorganic phase is washed with water and with saturated NaCl solution anddried over MgSO₄ and the solvent is evaporated off under vacuum. Theresidue is chromatographed on silica using a gradient of a DCM/MeOHmixture (99/1; v/v to 95/5; v/v) as the eluent. The product obtained isdissolved in DCM and acidified by the addition of ethereal hydrogenchloride and the precipitate formed is filtered off to give 0.2 g of theexpected product, m.p.=128° C.

EXAMPLE 53-[3-[4-(2-Aminothiazol-4-yl)-4-phenylpiperid-1-yl]propyl]-1-benzoyl-3-(3,4-dichlorophenyl)piperidinedihydrochloride monohydrate

A mixture of 1.04 g of 4-(2-aminothiazol-4-yl)-4-phenylpiperidine(compound of PREPARATION 1.4 in the form of the free base), 1.88 g ofthe compound obtained in step B of EXAMPLE 1 and 1.1 g of K₂ CO₃ in 20ml of a DMF/acetonitrile mixture (50/50; v/v) is refluxed for 2 hours.The reaction mixture is concentrated under vacuum, the residue is takenup with water and extracted with AcOEt, the organic phase is washed withwater and dried over MgSO₄ and the solvent is evaporated off undervacuum. The residue is chromatographed on silica using a gradient of aDCM/MeOH mixture (98/2; v/v to 95/5; v/v) as the eluent. The productobtained is taken up with ethereal hydrogen chloride and the precipitateformed is filtered off to give 1.2 g of the expected product aftercrystallization from AcOEt, m.p.=162-164° C.

EXAMPLE 63-[3-(4-Acetyl-4-benzylpiperid-1-yl)propyl]-1-benzoyl-3-(3,4-dichloro-phenyl)piperidinehydrochloride hemihydrate

1.2 g of 4-acetyl-4-benzylpiperidine hydrochloride are dissolved in theminimum amount of water, the solution is rendered alkaline to pH 13 bythe addition of concentrated NaOH solution and extracted with ether andthe organic phase is dried over MgSO₄ and filtered. 1 g of the compoundobtained in step B of EXAMPLE 1 is added to the filtrate and the mixtureis concentrated under vacuum. The residue is taken up with 5 ml of DMFand heated at 70° C. for 3 hours. The reaction mixture is poured intoiced water and extracted with ether, the organic phase is washed withwater and with saturated NaCl solution and dried over MgSO₄ and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica H using DCM and then a DCM/MeOH mixture (95/5; v/v) as theeluent. The product obtained is taken up with DCM and acidified to pH 1by the addition of ethereal hydrogen chloride and the mixture isevaporated under vacuum to give 0.84 g of the expected product aftercrystallization from iso ether.

Proton NMR spectrum at 200 MHz in DMSO-d₆

0.9 to 2.4 ppm: us: 15H

2.5 to 4.6 ppm: us: 12H

6.8 to 7.9 ppm: us: 13H

9.9 to 10.6 ppm: 2 bs: 1H

EXAMPLE 73-[3-[4-(Acetylamino)-4-benzylpiperid-1-yl]propyl]-1-benzoyl-3-(3,4-dichlorophenyl)piperidinehydrochloride dihydrate

A mixture of 0.44 g of 4-(acetylamino)-4-benzylpiperidinep-toluenesulfonate, 0.50 g of the compound obtained in step B of EXAMPLE1 and 0.53 g of K₂ CO₃ in 5 ml of DMF is heated at 90° C. for 2 hours.The reaction mixture is poured into water and extracted with AcOEt, theorganic phase is washed with 2 N NaOH and with saturated NaCl solutionand dried over MgSO₄ and the solvent is evaporated off under vacuum. Theresidue is chromatographed on silica H using a gradient of a DCM/MeOHmixture (99/1; v/v to 9317; v/v) as the eluent. The product obtained isdissolved in DCM and acidified by the addition of ethereal hydrogenchloride and the precipitate formed is filtered off to give 0.38 g ofthe expected product, m.p.=158° C. (dec.).

EXAMPLE 81-Benzoyl-3-[3-(4-benzyl-4-cyanopiperid-1-yl)propyl]-3-(3,4-dichlorophenyl)piperidinehydrochloride monohydrate

This compound is prepared by the procedure described in EXAMPLE 4,starting from 2.5 g of 4-benzyl-4-cyanopiperidine, 5 g of the compoundobtained in step B of EXAMPLE 1, 3.7 g of K₂ CO₃ and 50 ml of DMF. Theproduct obtained is chromatographed on silica H using DCM and then aDCM/MeOH mixture (97/3; v/v) as the eluent. The product obtained istaken up with ethereal hydrogen chloride and the solvent is evaporatedoff under vacuum to give 2.8 g of the expected product aftercrystallization from iso ether.

EXAMPLE 93-[3-[4-(Aminomethyl)-4-benzylpiperid-1-yl]propyl]-1-benzoyl-3-(3,4-dichlorophenyl)piperidinedihydrochloride hemihydrate

A mixture of 2.3 g of the compound obtained in EXAMPLE 8 and 0.3 g ofRaney® nickel in 100 ml of EtOH is hydrogenated for 72 hours at RT andat atmospheric pressure. The catalyst is filtered off and the filtrateis concentrated under vacuum. The residue is chromatographed on silica Husing DCM and then a DCM/MeOH mixture (8515; v/v) as the eluent. Theproduct obtained is taken up with ethereal hydrogen chloride and theprecipitate formed is filtered off to give 1.08 g of the expectedproduct.

Proton NMR spectrum at 200 MHz in DMSO-d₆

0.8to2.3 ppm: us: 12H

2.6 to 4.5 ppm: us: 14H

6.9 to 8.0 ppm: us: 13H

8.4 ppm: bs: 3H

EXAMPLE 101-Benzoyl-3-[3-[4-benzyl-4-(propionylaminomethyl)piperid-1-yl]propyl]-3-(3,4-dichlorophenyl)piperidinehydrochloride

A solution of 0.6 g of the compound obtained in EXAMPLE 9 and 0.18 ml oftriethylamine in 10 ml of DCM is cooled to 0° C., 0.1 ml of propionylchloride is added dropwise and the mixture is stirred for 5 minutes. Itis concentrated under vacuum, the residue is extracted with AcOEt, theorganic phase is washed twice with water and dried over MgSO₄ and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica H using DCM and then a DCM/MeOH mixture (95/5; v/v) as theeluent. The product obtained is taken up with ethereal hydrogen chlorideand the precipitate formed is filtered off to give 0.37 g of theexpected product.

Proton NMR spectrum at 200 MHz in DMSO-d₆

0.7to2.3 ppm: us: 17H

2.55 to 4.5 ppm: us: 14H

6.8 to 8.0 ppm: us: 14H

9.0 to 10 ppm: 2 bs: 1H

EXAMPLE 111-Benzoyl-3-[3-[4-benzyl-4-(ethoxycarbonylamino)piperid-1-yl]propyl]-3-(3,4-dichlorophenyl)piperidinehydrochloride hemihydrate

This compound is prepared by the procedure described in EXAMPLE 7,starting from 0.5 g of 4-benzyl-4-(ethoxycarbonylamino)piperidinep-toluenesulfonate, 0.5 g of the compound obtained in step B of EXAMPLE1 and 0.52 g of K₂ CO₃ in 5 ml of DMF. This gives 0.32 g of the expectedproduct, m.p.=142° C. (dec.).

EXAMPLE 121-Benzoyl-3-[3-[4-benzyl-4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]-3-(3,4-dichlorophenyl)piperidinehydrochloride hemihydrate

A mixture of 4-benzyl-4-(pyrrolidin-1-ylcarbonyl)piperidinep-toluenesulfonate, 0.65 g of the compound obtained in step B of EXAMPLE1 and 0.7 g of K₂ CO₃ in 6 ml of DMF is heated at 80° C. for 3 hours.The reaction mixture is poured into iced water and the precipitateformed is filtered off and washed with water. The precipitate isdissolved in AcOEt, the organic phase is dried over MgSO₄ and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica H using DCM and then a DCM/MeOH mixture (95/5; v/v) as theeluent. The product obtained is taken up with ethereal hydrogen chlorideand the precipitate formed is filtered off to give 0.56 g of theexpected product.

Proton NMR spectrum at 200 MHz in DMSO-d₆

0.9 to 2.45 ppm: us: 16H

2.5 to 4.6 ppm: us: 16H

6.8 to 7.8 ppm: us: 13H

9.9 to 10.6 ppm: rs: 1H

EXAMPLE 133-[3-[4-(Acetyl-N-methylamino)-4-phenylpiperid-1-yl]propyl]-1-benzoyl-3-(3,4-dichlorophenyl)perhydroazepinehydrochloride 0.3 hydrate

A)1-Benzoyl-3-(3,4-dichlorophenyl)-3-[3-(tetahydropyran-2-yloxy)propyl]-perhydroazepine

A solution of 13 g of the compound obtained in PREPARATION 2.2 and 6.8 gof triethylamine in 200 ml of DCM is cooled in an ice bath, a solutionof 4.96 g of benzoyl chloride in 30 ml of DCM is added dropwise and thereaction mixture is stirred for 5 minutes. It is concentrated undervacuum, the residue is taken up with water and extracted with AcOEt, theorganic phase is washed with water, with 5% NaHCO₃ solution, with waterand with saturated NaCl solution and dried over MgSO₄ and the solvent isevaporated off under vacuum to give 16.5 g of the expected product.

B) 1-Benzoyl-3-(3,4-dichlorophenyl)-3-(3-hydroxypropyl)perhydroazepine

A stream of HCl gas is bubbled into a solution of 16.5 g of the compoundobtained in the previous step in 200 ml of MeOH until the pH is <1, andthe reaction mixture is stirred for 10 minutes. It is concentrated undervacuum, the residue is taken up with a saturated solution of HCl gas inMeOH and the solvent is evaporated off under vacuum. The residue isextracted with DCM, the organic phase is washed with 5% NaHCO₃ solutionand with saturated NaCl solution and dried over MgSO₄ and the solvent isevaporated off under vacuum to give 13.7 g of the expected product.

C)1-Benzoyl-3-(3,4-dichlorophenyl)-3-[3-(methanesulfonyloxy)propyl]-perhydroazepine

A solution of 5 g of the compound obtained in the previous step and 1.5g of triethylamine in 100 ml of DCM is cooled in an ice bath, a solutionof 1.55 g of methanesulfonyl chloride in 20 ml of DCM is added dropwiseand the mixture is stirred for 5 minutes. It is concentrated undervacuum, the residue is taken up with water and extracted with AcOEt, theorganic phase is washed with water, with 5% NaHCO₃ solution, with waterand with saturated NaCl solution and dried over MgSO₄ and the solvent isevaporated off under vacuum to give 5.7 g of the expected product.

D)3-[3-[4-(Acetyl-N-methylamino)-4-phenylpiperid-1-yl]propyl]-1-benzoyl-3-(3,4-dichlorophenyl)perhydroazepinehydrochloride 0.3 hydrate

A mixture of 1.2 g of 4-(acetyl-N-methylamino)-4-phenylpiperidinep-toluenesulfonate, 1.2 g of the compound obtained in the previous stepand 1.2 g of K₂ CO₃ in 20 ml of a DMF/acetonitrile mixture (50/50; v/v)is refluxed for 3 hours. After cooling to RT, the reaction mixture ispoured into water and extracted with AcOEt, the organic phase is washedthree times with water and with saturated NaCl solution and dried overMgSO₄ and the solvent is evaporated off under vacuum. The residue ischromatographed on silica using DCM and then a DCM/MeOH mixture (96/4;v/v) as the eluent. The product obtained is taken up with etherealhydrogen chloride and the solvent is evaporated off under vacuum to give0.63 g of the expected product after solidification in ether, m.p.=125°C.

EXAMPLE 141-Benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(N,N-dimethylaminocarbonyl)-4-phenylpiperid-1-yl]propyl]perhydroazepinehydrochloride hemihydrate

This compound is prepared by the procedure described in step D ofEXAMPLE 13, starting from 0.69 g of4-(N,N-dimethylaminocarbonyl)-4-phenylpiperidine, 1.2 g of the compoundobtained in step C of EXAMPLE 13 and 1.2 g of K₂ CO₃ in 20 ml of aDMF/acetonitrile mixture (50/50; v/v). This gives 0.65 g of the expectedproduct, m.p.=150° C.

EXAMPLE 151-Benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-phenyl-4-(pyrrolidin-1-yl-carbonyl)piperid-1-yl]propyl]perhydroazepinehydrochloride hemihydrate

This compound is prepared by the procedure described in step D ofEXAMPLE 13, starting from 0.96 g of4-phenyl-4-(pyrrolidin-1-ylcarbonyl)-piperidine, 1.5 g of the compoundobtained in step C of EXAMPLE 13 and 1.5 g of K₂ CO₃ in 10 ml of aDMF/acetonitrile mixture (50/50; v/v). This gives 0.34 g of the expectedproduct, m.p.=135° C.

EXAMPLE 163-[3-[4-(2-Aminothiazol-4-yl)-4-phenylpiperid-1-yl-]propyl]-1-benzoyl-3-(3,4-dichlorophenyl)perhydroazepinedihydrochloride 1.5 hydrate

This compound is prepared by the procedure described in step D ofEXAMPLE 13, starting from 0.77 g of4-(2-aminothiazol-4-yl)-4-phenylpiperidine (compound of PREPARATION 1.4in the form of the free base), 1.2 g of the compound obtained in step Cof EXAMPLE 13 and 1.2 g of K₂ CO₃ in 20 ml of a DMF/acetonitrile mixture(50150; v/v). This gives 0.8 g of the expected product aftercrystallization from AcOEt, m.p.=178° C.

EXAMPLE 171-Benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(2-hydroxyethoxy)-4-phenylpiperid-1-yl]propyl]piperidinehydrochloride monohydrate

A mixture of 1 g of 4-(2-hydroxyethoxy)-4-phenylpiperidinehydrochloride, 1.7 g of the compound obtained in step B of EXAMPLE 1 and0.65 g of K₂ CO₃ in 15 ml of DMF is heated at 60° C. for 2 hours and thereaction mixture is then stirred overnight at RT. It is poured intowater and extracted with DCM, the organic phase is washed with water anddried over Na₂ SO₄ and the solvent is evaporated off under vacuum. Theresidue is chromatographed on silica H using DCM and then a DCM/MeOHmixture (96/4; v/v) as the eluent. The product obtained is dissolved inDCM and acidified by the addition of ethereal hydrogen chloride and theprecipitate formed is filtered off to give 1.2 g of the expectedproduct, m.p.=120-123° C.

EXAMPLE 183-[3-[4-(2-Acetoxyethoxy)-4-phenylpiperid-1-yl]propyl]-1-benzoyl-3-(3,4-dichlorophenyl)piperidinehydrochloride 1.5 hydrate

A solution of 0.6 g of the compound obtained in EXAMPLE 17 and 0.5 ml oftriethylamine in 25 ml of DCM is cooled to 0-5° C., 0.085 ml of acetylchloride is added and the mixture is stirred for 3 hours, thetemperature being allowed to rise to RT. It is concentrated undervacuum, the residue is taken up with water and extracted with AcOEt, theorganic phase is washed with water and dried over Na₂ SO₄ and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica using DCM and then a DCM/MeOH mixture (98/2; v/v) as theeluent. The product obtained is dissolved in DCM and acidified by theaddition of ethereal hydrogen chloride and the precipitate formed isfiltered off to give 1.2 g of the expected product, m.p.=105-107° C.

EXAMPLE 191-Benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(2-furoylamino)-4-phenylpiperid-1-yl]propyl]piperidinehydrochloride hemihydrate

A)3-[3-(4-Amino-4-phenylpiperid-1-yl)propyl]-1-benzoyl-3-(3,4-dichlorophenyl)-piperidine

A mixture of 6.81 g of 4-amino-4-phenylpiperidine dibenzenesulfonate,5.2 g of the compound obtained in step B of EXAMPLE 1 and 6.1 g of K₂CO₃ in 30 ml of a DMF/acetonitrile mixture (50/50; v/v) is heated at 100° C. for 5 hours. It is concentrated under vacuum, the residue istaken up with water and extracted with AcOEt, the organic phase iswashed with water and with saturated NaCl solution and dried over MgSO₄and the solvent is evaporated off under vacuum. The residue ischromatographed on silica H using a DCM/MeOH mixture (from 99/1; v/v to85/15; v/v) as the eluent to give 3.6 g of the expected product.

B)1-Benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(2-furoylamino)-4-phenylpiperid-1-yl]propyl]piperidinehydrochloride hemihydrate

A solution of 1.5 g of the compound obtained in the previous step and0.54 g of triethylamine in 10 ml of DCM is cooled to 0-5° C., 0.35 g of2-furoyl chloride is added and the mixture is stirred for 2 hours 30minutes, the temperature being allowed to rise to RT. It is concentratedunder vacuum, the residue is extracted with DCM, the organic phase iswashed with water, with 5% NaHCO₃ solution, with water and withsaturated NaCl solution and dried over MgSO₄ and the solvent isevaporated off under vacuum. The residue is chromatographed on silica Husing DCM and then a DCM/MeOH mixture (97/3; v/v) as the eluent Theproduct obtained is dissolved in AcOEt, a stream of HCl gas is bubbledinto the solution until the pH is 1, and ether is added untilprecipitation occurs. This gives 1.27 g of the expected product afterfiltration and drying, m.p.=180-182° C.

EXAMPLE 201-Benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(2-thenoylamino)-4-phenyl-piperid-1-yl]propyl]piperidinehydrochloride monohydrate

This compound is prepared by the procedure described in step B ofEXAMPLE 19, starting from 1.5 g of the compound obtained in step A ofEXAMPLE 19, 0.55 g of triethylamine and 0.4 g of 2-thenoyl chloride in10 ml of DCM. The residue is chromatographed on silica H using DCM andthen a DCM/MeOH mixture (95/5; v/v) as the eluent. The product obtainedis taken up with DCM and acidified to pH 1 by the addition of etherealhydrogen chloride and the precipitate obtained is filtered off to give0.99 g of the expected product, m.p.=198-200° C.

EXAMPLE 213-(3,4-Dichlorophenyl)-1-isonicotinoyl-3-[3-[4-phenyl-4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]piperidinedihydrochloride trihydrate, (+) isomer (compound of formula I.sup.•• a,Z.sup.•• =4-pyridyl)

A) 3-(3,4-Dichlorophenyl)-3-(3-hydroxypropyl)piperidine hydrochloride,(+) isomer

5 ml of 40% NaOH solution are added to a solution of 10 g of thecompound obtained in PREPARATION 2.1 in 20 ml of water, the mixture isextracted with DCM, the organic phase is dried over MgSO₄ and thesolvent is evaporated off under vacuum to give 9 g of an oil. 2.7 g ofthe oil obtained are dissolved in 50 ml of propan-2-ol, 2.36 g of10-camphosulfonic acid, (+) isomer, are added and the mixture is heatedto the reflux temperature. After cooling, crystallization and filtrationof the crystals formed (3.86 g), the latter are dissolved in 10% NaOHsolution and extracted with chloroform, the organic phase is dried overMgSO₄ and the solvent is evaporated off under vacuum to give 2.3 g ofproduct in the form of an oil, from which the hydrochloride is prepared.The optical rotation of the hydrochloride is measured.

[α]_(D) ²⁵ =+5.5° (c=0.1; MeOH)

A second crystallization is carried out using 2.12 g of the oil obtainedand 1.84 g of 10-camphosulfonic acid, (+) isomer, in 40 ml ofpropan-2-ol. After alkalization with NaOH, extraction with chloroform,drying over MgSO₄ and evaporation, 2.1 g of the expected product areobtained in the form of an oil, from which the hydrochloride isprepared.

[α]_(D) ²⁵ =+6.5° (c=0. 1; MeOH)

B)1-(tert-Butoxycarbonyl)-3-(3,4-dichlorophenyl)-3-(3-hydroxypropyl)piperidine,(+) isomer

0.61 g of di-tert-butyl dicarbonate is added to a solution of 0.9 g ofthe compound obtained in the previous step and 0.6 g of triethylamine in100 ml of DCM and the mixture is stirred for 30 minutes at RT. It isconcentrated under vacuum, the residue is extracted with AcOEt, theorganic phase is washed with a buffer solution of pH 2, with 1 N NaOHsolution and with saturated NaCl solution and dried over MgSO₄ and thesolvent is evaporated off under vacuum to give 1.1 g of the expectedproduct in the form of an oil.

C)1-(tert-Butoxycarbonyl)-3-(3,4-dichlorophenyl)-3-[3-(methanesulfonyloxy)-propyl]piperidine,(+) isomer

A solution of 22 g of the compound obtained in the previous step and6.86 g of triethylamine in 150 ml of DCM is cooled to 0-5° C., 7.13 g ofmethanesulfonyl chloride are added and the mixture is stirred for 1 hourat 0-5° C. and then for 2 hours at RT. It is concentrated under vacuum,the residue is extracted with AcOEt, the organic phase is washed withwater and with saturated NaCl solution and dried over MgSO₄ and thesolvent is evaporated off under vacuum. The product obtained is taken upwith ether and the mixture is then evaporated under vacuum to give 26.4g of the expected product in the form of an oil.

D)1-(tert-Butoxycarbonyl)-3-(3,4-dichlorophenyl)-3-[3-[4-phenyl-4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]piperidine,(+) isomer

A mixture of 17 g of 4-phenyl-4-(pyrrolidin-1-ylcarbonyl)piperidine,25.5 g of the compound obtained in the previous step and 22.7 g of K₂CO₃ in 100 ml of a DMF/acetonitrile mixture (50/50; v/v) is heated at100° C. for 3 hours 30 minutes. It is concentrated under vacuum, theresidue is extracted with AcOEt, the organic phase is washed with waterand with saturated NaCl solution and dried over MgSO₄ and the solvent isevaporated off under vacuum. The residue is taken up with pentane andthe precipitate formed is filtered off to give 33 g of the expectedproduct, m.p.=133-137° C.

[α]_(D) ²⁰ =+33.2° (c=0.5; MeOH)

E)3-(3,4-Dichlorophenyl)-3-[3-[4-phenyl-4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]piperidinedihydrochloride, (+) isomer

Concentrated HCl solution is added to a solution of 25.8 g of thecompound obtained in the previous step in 200 ml of MeOH until the pH is1, and the mixture is heated at 40° C. for 3 hours. It is concentratedunder vacuum and the product obtained is crystallized from anAcOEt/ether mixture to give 17 g of the expected product, m.p.=170° C.

[α]_(D) ²⁰ =+13° (c=0.5; MeOH)

F)3-(3,4-Dichlorophenyl)-1-isonicotinoyl-3-[3-[4-phenyl-4-(pyrrolidin-1-yl-carbonyl)piperid-1-yl]propyl]piperidinedihydrochloride tihydrate, (+) isomer

A solution of 1.7 g of the compound obtained in the previous step and0.9 g of triethylamine in 10 ml of DCM is cooled to 0-5° C., 0.6 g ofisonicotinoyl chloride hydrochloride is added and the mixture is stirredfor 1 hour at RT. It is concentrated under vacuum, the residue isextracted with AcOEt, the organic phase is washed with water and withsaturated NaCl solution and dried over Na₂ SO₄ and the solvent isevaporated off under vacuum. The residue is chromatographed on silica Husing DCM and then a DCM/MeOH mixture (93/7; v/v) as the eluent. Theproduct obtained is dissolved in AcOEt, a stream of HCl gas is bubbledinto the solution until the pH is 1, and ether is added untilprecipitation occurs. This gives 0.27 g of the expected product afterfiltration and drying, m.p.=140-142° C.

[α]_(D) ²⁰ =+11.6° (c 0.5; MeOH)

EXAMPLE 221-Benzoyl-3-(3,4-dichlorophenyl)-3-[3-[spiro(indoline-3,4'-piperid-1'-yl)]-propyl]piperidinedihydrochloride 1.5 hydrate

A mixture of 1 g of the compound obtained in step B of EXAMPLE 1, 0.7 gof spiro(indoline-3,4'-piperidine) dihydrochloride and 0.8 g of K₂ CO₃in 10 ml of DMF is heated at 70-80° C. for 3 hours. The reaction mixtureis poured into water and the precipitate formed is filtered off anddried. The precipitate is chromatographed on silica using DCM and then aDCM/MeOH mixture (94/6; v/v) as the eluent. The product obtained isdissolved in DCM and acidified to pH 1 by the addition of etherealhydrogen chloride and the precipitate formed is filtered off to give 0.5g of the expected product, m.p.=192-195° C.

EXAMPLE 231-Benzoyl-3-(3,4-dichlorophenyl)-3-[3-[1-acetylspiro(indoline-3,4'-piperid-1'-yl)propyl]piperidinehydrochloride monohydrate

A mixture of 1 g of the compound obtained in step B of EXAMPLE 1, 1 g of1-acetylspiro(indoline-3,4'-piperidine) hydrochloride and 0.6 g of K₂CO₃ in 10 ml of DMF is heated at 70° C. for 2 hours. The reactionmixture is poured into water and the precipitate formed is filtered off.The precipitate is dissolved in DCM, the organic phase is dried overMgSO₄ and the solvent is evaporated off under vacuum. The residue ischromatographed on silica using DCM and then a DCM/MeOH mixture (97/3;v/v) as the eluent. The product obtained is dissolved in DCM andacidified to pH 1 by the addition of ethereal hydrogen chloride and theprecipitate formed is filtered off to give 0.7 g of the expectedproduct, m.p.=189-191° C.

The compounds according to the invention collated in TABLE I below areprepared by following the procedure described in step F of EXAMPLE 21,staring from the compound obtained in step E of EXAMPLE 21 and theappropriate acid chlorides.

                  TABLE I                                                         ______________________________________                                                                      (I.sup.•• a)                                                        #STR121##                                        -                                                                                                Salt, solvate;                                              m.p. ° C.;                                                           Example Z.sup.•• [α].sub.D.sup.20                         ______________________________________                                          24                                                                                                  HCl, 1H##                                                                   .sub.2 O;  134-136;  +31° (c = 0.5; MeOH)                                - 25                                                                          HCl, 0.5H.sub.2 O;  172;  +35.6° (c = 0.5;                           MeOH)                                                      - 26                                                                                               HCl, 1.25H.sub.2 O;  120-122;  +47° (c =                             0.5; MeOH)                                                 - 27                                                                                               HCl, 2H.sub.2 O;  175;  +32.6° (c = 0.5;                             MeOH)                                                   ______________________________________                                    

The compounds according to the invention collated in TABLE II below areprepared by following the procedures described in the previous EXAMPLES,starting from the compound obtained in step B of EXAMPLE 1 and thepiperidines described in the PREPARATIONS.

                  TABLE II                                                        ______________________________________                                                                       (I)                                                                             #STR126##                                                                  Salt, solvate;                                      m.p. ° C.                                                            Example B-- or NMR                                                          ______________________________________                                          28  (a)                                                                                                     2HCl, 2.5H                                                                  .sub.2 O;  202-204                                 - 29  (b)                                                                                                  HCl, H.sub.2 O;  160-162                         - 30  (a)                                                                                                  2HCl, H.sub.2 O;  165                            - 31  (c)                                                                                                  HCl, 1.2H.sub.2 O;  175-180                      - 32  (c)                                                                                                  HCl, 0.5H.sub.2 O;  155-157                      - 33  (c)                                                                                                  HCl, 1.3H.sub.2 O;  158-160                   ______________________________________                                         (a) This compound is prepared by the procedure described in EXAMPLE 2.        (b) This compound is prepared by the procedure described in step B of         EXAMPLE 19, starting from the compound obtained in step A of EXAMPLE 19       and ethyloxalyl chloride.                                                     (c) This compound is prepared by the procedure described in EXAMPLE 23,       starting from the compound obtained in step B of EXAMPLE 1 and the            appropriate spiro(indoline3,4'-piperidines).                             

We claim:
 1. A compound of the formula ##STR133## in which: R₁ ishydrogen;R₂ is the methyl group; or R₁ and R₂ together form a group--(CH₂)₃ --; Ar₁ is a phenyl which is unsubstituted or monosubstitutedor polysubstituted by a substituent selected from a halogen atom, ahydroxyl, a (C₁ -C₄)alkoxy, a (C₁ -C₄)alkyl, a trifluoromethyl and amethylenedioxy, said substituents being identical or different; athienyl which is unsubstituted or substituted by a halogen atom; abenzothienyl which is unsubstituted or substituted by a halogen atom; anaphthyl which is unsubstituted or substituted by a halogen atom; anindolyl which is unsubstituted or N-substituted by a (C₁ -C₄)alkyl or abenzyl; an imidazolyl which is unsubstituted or substituted by a halogenatom; a pyridyl which is unsubstituted or substituted by a halogen atom;or a biphenyl; T is a group --CH₂ --; a group --CO--; a group --COO--;or a group --CONR₃ -- in which R₃ is a hydrogen or a (C₁ -C₄)alkyl; A isa direct bond; a group --(CH₂)_(t) --, in which t is one, two or three;or a vinylene group; or --T--A-- is the group --SO₂ --; Z is anoptionally substituted, mono-, di- or tri-cyclic aromatic orheteroaromatic group; and B is: i--either a group B₁ of the formula##STR134## in which J₁ is: i₁ --either a group ##STR135## in which: x iszero or one; Ar₂ is a phenyl which is unsubstituted or monosubstitutedor polysubstituted by a substituent selected from a halogen atom, anitro, a hydroxyl, a trifluoromethyl, a (C₁ -C₄)alkyl, a (C₁ -C₄)alkoxyand a methylenedioxy, said substituents being identical or different; apyridyl; a thienyl; a pyrimidyl; or an imidazolyl which is unsubstitutedor substituted by a (C₁ -C₄)alkyl; and X₁ is a group selected from:(1)hydrogen; (2) (C₁ -C₇)alkyl; (3) formyl; (4) (C₁ -C₇)alkylcarbonyl; (5)--(CH₂)_(m) --OR₄ ; (6) --(CH₂)_(m) --OCOR₅ ; (7) --(CH₂)_(m)--OCONH--(C₁ -C₇)alkyl; (8) --O--CH₂ CH₂ --OR₆ ; (9) --(CH₂)_(n) --SR₇ ;(10) --CH₂ --S(O)_(j) --(C₁ -C₇)alkyl; (11) --NR₈ R₉ ; (12) --(CH₂)_(p)--NR₁₀ R₁₁ ; (13) --NR₁₂ COR₁₃ ; (14) --NR₁₄ COCOR₁₅ ; (15) --(CH₂)_(p)--NR₁₄ C(═W₁)R₁₆ ; (16) --(CH₂)_(m) --NR₁₄ COOR₁₇ ; (17) --(CH₂)_(m)--NR₁₄ SO₂ R₁₈ ; (18) --(CH₂)_(m) --NR₁₄ C(═W₁)NR₁₉ R₂₀ ; (19)--(CH₂)_(n) --COOR₂₁ ; (20) --(CH₂)_(n) --C(═W₁)NR₁₉ R₂₀ ; (21)--CO--NR₂₂ --NR₂₃ R₂₄ ; (22) --CN; ##STR136## or X₁ forms a double bondbetween the carbon atom to which it is bonded and the adjacent carbonatom of the piperidine ring; in which groups:m is zero, one or two; n iszero or one; p is one or two; j is one or two; W₁ is an oxygen atom or asulfur atom; R₄ is a hydrogen or a (C₁ -C₇)alkyl; R₅ is a hydrogen; a(C₁ -C₇)alkyl; a (C₃ -C₇)cycloalkyl which is unsubstituted orsubstituted by one or more methyls; a phenyl; or a pyridyl; R₆ is ahydrogen; a (C₁ -C₇)alkyl; a formyl; or a (C₁ -C₇)alkylcarbonyl; R₇ is ahydrogen or a (C₁ -C₇)alkyl; R₈ and R₉ are each independently a hydrogenor a (C₁ -C₇)alkyl; R₉ can also be a (C₃ -C₇)cycloalkylmethyl, a benzylor a phenyl; or R₈ and R₉, together with the nitrogen atom to which theyare bonded, form a heterocycle selected from azetidine, pyrrolidine,piperidine, morpholine, thio-morpholine, perhydroazepine and piperazinewhich is unsubstituted or substituted in the 4-position by a (C₁-C₄)alkyl; R₁₀ and R₁₁ are each independently a hydrogen or a (C₁-C₇)alkyl; R₁₁ can also be a (C₃ -C₇)cycloalkylmethyl or a benzyl; R₁₂is a hydrogen or a (C₁ -C₇)alkyl; R₃ is a hydrogen; a (C₁ -C₇)alkyl; a(C₃ -C₇)cycloalkyl which is unsubstituted or substituted by one or moremethyls; a phenyl; a benzyl; a vinyl; a pyridyl; a firyl; a thienyl; apyrrolyl; or an imidazolyl; or R₁₂ and R₁₃ together are a group--(CH₂)_(u) --, in which u is three or four; R₁₄ is a hydrogen or a (C₁-C₇)alkyl; R₁₅ is a (C₁ -C₄)alkoxy; R₁₆ is a hydrogen; a (C₁ -C₇)alkyl;a (C₃ -C₇)cycloalkyl which is unsubstituted or substituted by one ormore methyls; a phenyl; a benzyl; a vinyl; a pyridyl; a furyl; athienyl; a pyrrolyl; or an imidazolyl; R₁₇ is a (C₁ -C₇)alkyl or aphenyl; R₁₈ is a (C₁ -C₇)alkyl; an amino which is free or substituted byone or two (C₁ -C₇)alkyls; or a phenyl which is unsubstituted ormonosubstituted or polysubstituted by a substituent selected from ahalogen atom, a (C₁ -C₇)alkyl, a trifluoromethyl, a hydroxyl, a (C₁-C₇)alkoxy, a carboxyl, a (C₁ -C₇)alkoxycarbonyl, a (C₁-C₇)alkylcarbonyloxy, a cyano, a nitro and an amino which is free orsubstituted by one or two (C₁ -C₇)alkyls, said substituents beingidentical or different; R₁₉ and R₂₀ are each independently a hydrogen ora (C₁ -C₇)alkyl; R₂₀ can also be a (C₃ -C₇)cycloalkyl; a (C₃-C₇)cycloalkylmethyl; a hydroxyl; a (C₁ -C₄)alkoxy; a benzyl; a phenyl;or a (C₁ -C₇)alkyl substituted by a hydroxyl, a (C₁ -C₃)alkoxy, aphenyl, a carboxyl, a (C₁ -C₃)alkoxycarbonyl or a carbamoyl which isunsubstituted or substituted by one or two (C₁ -C₇)alkyls; or R₁₉ andR₂₀, together with the nitrogen atom to which they are bonded, form aheterocycle selected from azetidine, pyrrolidine, piperidine,morpholine, thio-morpholine, perhydroazepine and piperazine which isunsubstituted or substituted in the 4-position by a (C₁ -C₄)alkyl; R₂₁is a hydrogen or a (C₁ -C₇)alkyl; R₂₂ is a hydrogen or a (C₁ -C₇)alkyl;R₂₃ and R₂₄ are each independently a hydrogen or a (C₁ -C₇)alkyl; R₂₅ isa hydrogen or a (C₁ -C₇)alkyl; and R₂₆ and R₂₇ are each independently ahydrogen or a (C₁ -C₇)alkyl; R₂₇ can also be a formyl or a (C₁-C₇)alkylcarbonyl; i₂ --or a group ##STR137## in which Ar₂ is as definedabove; i₃ --or a group ##STR138## in which Ar₂ is as defined above; i₄--or a group ##STR139## in which Ar₂ is as defined above; i₅ --or agroup ##STR140## in which: Ar₂ is as defined above; Am₁ is an aminogroup substituted by two (C₁ -C₄)alkyls; and r is two or three; i₆ --ora group ##STR141## in which: Ar₂ is as defined above; W₂ is an oxygenatom; a sulfur atom; a sulfinyl; a sulfonyl; or a group --NL₁ --; L₁ isa hydrogen; a (C₁ -C₄)alkyl; a (C₁ -C₄)alkylcarbonyl; or a group--(CH₂)_(v) --Am₂ ; v is one, two or three; and Am₂ is an amino groupwhich is unsubstituted or monosubstituted or disubstituted by a (C₁-C₄)alkyl; Am₂ can also be apyrrolidino, oiperidino or morpholino group;ii--or a group B₃ of the formula ##STR142## in which J₃ is: a group:##STR143## in which: W₃ is an oxygen atom; a sulfar atom; or a groupNR₃₀, in which R₃₀ is a hydrogen or a (C₁ -C₃)alkyl;R₂₈ is a hydrogen; a(C₁ -C₆)alkyl; a (C₃ -C₆)alkenyl in which one vinylic carbon atom is notbonded to the nitrogen atom; a 2-hydroxyethyl; a (C₃ -C₇)cycloalkyl; aphenyl which is unsubstituted or monosubstituted or polysubstituted by asubstituent selected from a halogen atom, a trifluoromethyl, a (C₁-C₄)alkyl, a (C₁ -C₄)alkoxy, a nitro, an amino and a hydroxyl, saidsubstituents being identical or different; or a 6-membered heteroarylcontaining one or two nitrogen atoms as heteroatoms, said heteroarylbeing unsubstituted or monosubstituted or polysubstituted by asubstituent selected from a halogen atom, a trifluoromethyl, a (C₁-C₄)alkyl, a (C₁ -C₄)alkoxy, a nitro, an amino and a hydroxyl, saidsubstituents being identical or different; R₂₉ is a hydrogen; a (C₁-C₆)alkyl which is unsubstituted or substituted by a hydroxyl and/or byone, two or three fluorine atoms; a (C₃ -C₆)cycloalkyl; a (C₁ -C₅)alkoxy(only when W₃ is an oxygen atom); a (C₃ -C₆)cycloalkoxy (only when W₃ isan oxygen atom); or a group --NR₃₁ R₃₂ containing from zero to sevencarbon atoms, R₂₉ being other than an unsubstituted (C₁ -C₄)alkyl whensimultaneously W₃ is an oxygen and R₂₈ is a phenyl which isunsubstituted or monosubstituted or polysubstituted by a substituentselected from a halogen atom, a nitro, a hydroxyl, a trifluoromethyl, a(C₁ -C₄)alkyl and a (C₁ -C₄)alkoxy, said substituents being identical ordifferent; a pyridyl; or a pyrimidyl; or R₂₈ and R₂₉ together form adivalent hydrocarbon group L₂, in which the 1-position is bonded to thecarbon atom carrying the substituent W₃, the divalent hydrocarbon groupL₂ being selected from a trimethylene, a cis-propenylene, atetramethylene, a cis-butenylene, a cis,cis-butadienylene, apentamethylene and a cis-pentenylene, said divalent hydrocarbon group L₂being unsubstituted or substituted by one or two methyls; and R₃₁ andR₃₂ are each independently a hydrogen, a (C₁ -C₅)alkyl or a (C₃-C₆)cycloalkyl; or R₃₁ and R₃₂, together with the nitrogen atom to whichthey are bonded, form a heterocycle selected from pyrrolidine,piperidine, morpholine, thiomorpholine (or its S-oxide) and piperazinewhich is unsubstituted or substituted in the 4-position by a (C₁-C₄)alkyl; iii--or a group B₄ of the formula ##STR144## in which: W₄ isa (C₁ -C₈)alkyl or a (C₃ -C₈)cycloalkyl, said alkyl and cycloalkylgroups being unsubstituted or substituted by one or more substituentsselected from a halogen atom; a (C₃ -C₆)cycloalkyl; a cyano; a nitro; ahydroxyl; a (C₁ -C₄)alkoxy, a formyloxy; a (C₁ -C₄)alkylcarbonyloxy; anarylcarbonyl; a heteroarylcarbonyl; an oxo; an imino which isunsubstituted or substituted on the nitrogen atom by a (C₁ -C₆)alkyl, a(C₃ -C₆)cycloalkyl, a formyl, a (C₁ -C₄)alkylcarbonyl or anarylcarbonyl; a hydroxyimino which is unsubstituted or substituted onthe oxygen atom by a (C₁ -C₄)alkyl or a phenyl; a group --NR₃₃ R₃₄containing from zero to seven carbon atoms; a group --NR₃₅ R₃₆ ; a group--C(═NR₃₇)NR₃₈ R₃₉, in which the group --NR₃₈ R₃₉ contains from zero toseven carbon atoms; and a group --CON(OR₄₀)R₄₁, said substituents beingidentical or different; R₃₃ and R₃₄ are each independently a hydrogen, a(C₁ -C₅)alkyl or a (C₃ -C₆)cycloalkyl; or R₃₃ and R₃₄, together with thenitrogen atom to which they are bonded, form a heterocycle selected frompyrrolidine, piperidine, morpholine, thiomorpholine (or its S-oxide) andpiperazine which is unsubstituted or substituted in the 4-position by a(C₁ -C₄)alkyl; R₃₅ is a hydrogen or a (C₁ -C₄)alkyl; R₃₆ is a formyl; a(C₁ -C₄)alkylcarbonyl; an arylcarbonyl; a heteroarylcarbonyl; or a group--C(═W₅)NR₃₈ R₃₉, in which the group --NR₃₈ R₃₉ contains from zero toseven carbon atoms; W₅ is an oxygen atom; a sulfur atom; a group NR₃₇ ;or a group CHR₄₂ ; R₃₇ is a hydrogen or a (C₁ -C₄)alkyl; or R₃₇ and R₃₉together form an ethylene group or a trimethylene group; R₃₈ and R₃₉ areeach independently a hydrogen, a (C₁ -C₅)alkyl or a (C₃ -C₆)cycloalkyl;or R₃₈ and R₃₉, together with the nitrogen atom to which they arebonded, form a heterocycle selected from pyrrolidine, piperidine,morpholine, thiomorpholine (or its S-oxide) and piperazine which isunsubstituted or substituted in the 4-position by a (C₁ -C₄)alkyl; orR₃₈ is a hydrogen or a (C₁ -C₄)alkyl and R₃₉ and R₃₇ together form anethylene group or a trimethylene group; R₄₀ and R₄₁ are eachindependently a (C₁ -C₃)alkyl; R₄₂ is a cyano; a nitro; or a group SO₂R₄₃ ; R₄₃ is a (C₁ -C₄)alkyl or a phenyl; and when W₄ is a cyclic groupor when a substituent of W₄ is a cyclic group or contains a cyclicgroup, said cyclic groups can also be substituted on a carbon atom byone or more (C₁ -C₃)alkyls; and when a substituent of W₄ contains anaryl group or a heteroaryl group, said aryl or heteroaryl groups canalso be monosubstituted or polysubstituted by a substituent selectedfrom a halogen atom, a (C₁ -C₄)alkyl, a (C₁ -C₄)alkoxy, a cyano, atrifluoromethyl and a nitro, said substituents being identical ordifferent; iv--or a group B₅ of the formula ##STR145## in which: W₆ andW₇ are each a hydrogen; or W₆ is a hydrogen and W₇ is a hydroxyl; W₈ isan aryl or a heteroaryl which are unsubstituted or substituted by anaryl, an arylcarbonyl, a heteroaryl or a heteroarylcarbonyl; said arylor heteroaryl groups can also be monosubstituted or polysubstituted onthe aromatic or heteroaromatic moiety and on a carbon atom by asubstituent selected from a halogen atom; a cyano; a trifluoromethyl; anitro; a hydroxyl; a (C₁ -C₅)alkoxy; a formyloxy, a (C₁-C₄)alkylcarbonyloxy; a group --NR₃₃ R₃₄ containing from zero to sevencarbon atoms; a group --NR₃₅ R₃₆ ; a group --C(═NR₃₇)NR₃₈ R₃₉, in whichthe group --NR₃₈ R₃₉ contains from zero to seven carbon atoms; a group--COOR₄₄ ; a group --CONR₄₅ R₄₆, in which the group NR₄₅ R₄₆ containsfrom zero to seven carbon atoms; a mercapto; a group --S(O)_(s) R₄₇ ; a(C₁ -C₅)alkyl; a formyl; and a (C₁ -C₄)alkylcarbonyl, said substituentsbeing identical or different; when W₆ and W₇ are each a hydrogen, W₈ isother than a phenyl which is unsubstituted or monosubstituted orpolysubstituted by a substituent selected from a halogen atom, a nitro,a hydroxyl, a trifluoromethyl and a (C₁ -C₄)alkoxy, said substituentsbeing identical or different; a pyridyl; a thienyl; a pyrimidyl; or animidazolyl which is unsubstituted or substituted by a (C₁ -C₄)alkyl; orW₇ is a hydrogen and W₆ and W₈, together with a diradical W₉ and thepiperidine carbon atom to which they are bonded, form a spiro ring inwhich W₈ is a phenyl substituted in the ortho position by a diradicalW₉, which is itself joined to W₆, said phenyl being unsubstituted orsubstituted by a substituent selected from a halogen atom, a (C₁-C₃)alkyl, a (C₁ -C₃)alkoxy, a hydroxyl, a (C₁ -C₃)alkylthio, a (C₁-C₃)alkxylsulfinyl and a (C₁ -C₃)alkylsulfonyl; the diradical W₉ is amethylene, a carbonyl or a sulfonyl; and W₆ is an oxygen atom or a group--NR₄₈ --, in which R₄₈ is a hydrogen or a (C₁ -C₃)alkyl; R₃₃, R₃₄, R₃₅,R₃₆, R₃₇, R₃₈ and R₃₉ are as defined above for the group B₄ ; R₄₄ is ahydrogen; a (C₁ -C₅)alkyl; an aryl; a heteroaryl; an arylmethyl; or aheteroarylmethyl; R₄₅ and R₄₆ are each independently a hydrogen, a (C₁-C₅)alkyl or a (C₃ -C₆)cycloalkyl; or R₄₅ and R₄₆, together with thenitrogen atom to which they are bonded, form a heterocycle selected frompyrrolidine, piperidine, morpholine, thiomorpholine (or its S-oxide) andpiperazine which is unsubstituted or substituted in the 4-position by a(C₁ -C₄)alkyl; s is zero, one or two; R₄₇ is a (C₁ -C₆)alkyl; a (C₃-C₆)cycloalkyl; an aryl; or a heteroaryl; and when W₈ or a substituentof W₈ contains a cyclic group, said cyclic group can also be substitutedby one or more methyls; and when a heteroaryl group forming part of W₈or of a substituent of W₈ contains a nitrogen atom as the heteroatom,said nitrogen atom can also be substituted by a (C₁ -C₅)alkyl; and whenW₈ or a substituent of W₈ contains a (C₁ -C₅)alkyl, (C₁ -C₅)alkoxy,formyl or (C₁ -C₄)alkylcarbonyl group, said (C₁ -C₅)alkyl, (C₁-C₅)alkoxy, formyl or (C₁ -C₄)alkylcarbonyl groups can also besubstituted by a hydroxyl, a (C₁ -C₃)alkoxy or one or more halogenatoms, with the proviso that a carbon atom bonded to a nitrogen atom orto an oxygen atom is not substituted by a hydroxyl or an alkoxy group,and with the proviso that a carbon atom in the α-position of a (C₁-C₄)alkylcarbonyl group is not substituted by a chlorine, bromine oriodine atom; v--or a group B₆ of the formula ##STR146## in which J₄ is:vi₁ --either a group ##STR147## in which: W₁₀ is a phenyl which isunsubstituted or monosubstituted to trisubstituted by a substituentselected from a halogen atom, a (C₁ -C₆)alkoxy, a (C₁ -C₆)alkyl and atrifluoromethyl, said substituents being identical or different; abenzyl which is unsubstituted or monosubstituted to trisubstituted by asubstituent selected from a halogen atom, a (C₁ -C₆)alkoxy, a (C₁-C₆)alkyl and a trifluoromethyl, said substituents being identical ordifferent; a naphthyl which is unsubstituted or monosubstituted totrisubstituted by a substituent selected from a halogen atom, a (C₁-C₆)alkoxy, a (C₁ -C₆)alkyl and a trifluoromethyl, said substituentsbeing identical or different; a pyridyl which is unsubstituted ormonosubstituted or disubstituted by a substituent selected from ahalogen atom, a (C₁ -C₆)alkyl and a (C₁ -C₆)alkoxy, said substituentsbeing identical or different; a thienyl; a pyrimidyl; or an imidazolyl;and W₁₁ is a group --CONHR₄₉ ; R₄₉ is a group ##STR148## a group##STR149## a group --CH₂ CH₂ N(CH₃)₂ ; vi₂ --or a group: ##STR150## vi₃--or a group: ##STR151## vi₄ --or a group: ##STR152## in which: R₅₀ is ahydrogen, a (C₁ -C₆)alkyl or a benzyl; and R₅₁ is from one to threesubstituents selected from a hydrogen, a halogen atom, atrifluoromethyl, a (C₁ -C₆)alkyl and a (C₁ -C₆)alkoxy, said substituentsbeing identical or different; vi--or a group B₈ of the formula##STR153## in which: W₁₇ is a direct bond; a double bond; or a divalenthydrocarbon radical; W₁₈ is a radical which is joined to the carbon atomof the heterocycle either by a single bond when W₁₇ is a double bond, orby a double bond in the other cases; W₁₉ is an unsubstituted oroptionally substituted heteroatom; W₂₀ is a hydrocarbon radical of whichthe 1-position is joined to W₁₉ ; and the meanings of W₁₇, W₁₈, W₁₉ andW₂₀ are selected from:(a) W₁₇ is a direct bond; W₁₈ is an oxo or thioxogroup; W₁₉ is an oxy or thio group or a group NR₅₉ ; and W₂₀ is ahydrocarbon radical L₃ ; or (b) W₁₇ is a direct bond; W₁₈ is a groupNR₆₀ ; W₁₉ is a group NR₆₁ ; and W₂₀ is a hydrocarbon radical L₃ ; or(c) W₁₇ is a double bond; W₁₈ is a group OR₆₁, SR₆₁ or NR₆₂ R₆₃ ; W₁₉ isa nitrogen atom; and W₂₀ is a hydrocarbon radical L₃ ; or (d) W₁₇ is amethylene which is unsubstituted or substituted by one or two methylgroups; W₁₈ is an oxo or thioxo group or a group NR₆₄ ; W₁₉ is an oxy,thio, sulfinyl or sulfonyl group or a group NR₆₁ ; and W₂₀ is ahydrocarbon radical L₄ ; or (e) W₁₇ is a direct bond; W₁₈ is an oxo orthioxo group or a group NR₆₄ ; W₁₉ is a nitrogen atom; and W₂₀ is ahydrocarbon radical L₅ ; or (f) W₁₇ is a methine group which isunsubstituted or substituted by one or two methyl groups; W₁₈ is an oxoor thioxo group or a group NR₆₄ ; W₁₉ is a nitrogen atom; and W₂₀ is ahydrocarbon radical L₆ ; and (g) W₁₇ is a cis-vinylene group which isunsubstituted or substituted by one or two methyl groups; W₁₈ is an oxoor thioxo group or a group NR₆₄ ; W₁₉ is a nitrogen atom; and W₂₀ is ahydrocarbon radical L₇ ; R₅₉ is a hydrogen; a (C₁ -C₃)alkyl; a group--CH₂ COOR₆₅ ; or a group --CH₂ CONR₆₆ R₆₇ ; R₆₉ is a hydrogen; a (C₁-C₃)alkyl; a cyano; a nitro; or a (C₁ -C₃)alkylsulfonyl group; R₆₁ is ahydrogen or a (C₁ -C₃)alkyl; R₆₂ and R₆₃ are each independently ahydrogen or a (C₁ -C₃)alkyl; or R₆₂ and R₆₃, together with the nitrogenatom to which they are bonded, form a heterocycle selected frompyrrolidine, piperidine, morpholine, thiomorpholine (or its S-oxide) andpiperazine which is unsubstituted or substituted in the 4-position by a(C₁ -C₄)alkyl; R₆₄ is a hydrogen or a (C₁ -C₃)alkyl; R₆₅ is a hydrogenor a (C₁ -C₃)alkyl; R₆₆ and R₆₇ are each independently a hydrogen; a (C₁-C₃)alkyl; a phenyl; or a benzyl; L₃ is an ethylene, a cis-vinylene, atrimethylene or a tetramethylene, said hydrocarbon radical L₃ beingunsubstituted or substituted by one or two methyl groups; L₄ is anethylene or a trimethylene, said hydrocarbon radical L₄ beingunsubstituted or substituted by one or two methyl groups; L₅ is aprop-2-en-1-yliden-3-yl which is unsubstituted or substituted by one ortwo methyl groups; L₆ is a cis-vinylene which is unsubstituted orsubstituted by one or two methyl groups; and L₇ is a methine which isunsubstituted or substituted by a (C₁ -C₃)alkyl; vii--or a group B₉ ofthe formula ##STR154## in which J₅ is: a group ##STR155## in which: X₂is a (C₁ -C₆)alkyl; a group --CH₂ --OR₆₈ ; a group --CH₂ --SR₆₈ ; agroup --CH₂ --S(O)R₆₉ ; a group --CH₂ --SO₂ R₆₉ ; a group --COOR₆₈ ; agroup --C(═W₂₄)NR₇₀ R₇₁ ; a group --C(R₆₈)(OR₇₂)(OR₇₃); a group --CH₂NR₆₈ C(═W₂₄)R₇₄ ; a group --CH₂ --NR₆₈ COOR₇₄ ; or a group --CH₂ NR₆₈C(═W₂₄)NR₇₀ R₇₁ ; W₂₁ is a direct bond and W₂₂ is a hydrocarbon radicalof which the 1-position is joined to W₂₁, the hydrocarbon radical W₂₂being selected from a trimethylene, a tetramethylene, a cis-1-butenyleneand a cis,cis-butadienylene; or W₂₁ is a group NR₇₅ and W₂₂ is ahydrocarbon radical selected from an ethylene, a trimethylene and acis-vinylene; or W₂₁ is a nitrogen atom and W₂₂ is acis,cis-prop-2-en-1-yliden-3-yl radical of which the 1-position isjoined to W₂₁ ; W₂₃ is an oxygen atom or a sulfur atom; W₂₄ is an oxygenatom or a sulfur atom; R₆₈ is a hydrogen or a (C₁ -C₆)alkyl; R₆₉ is a(C₁ -C₆)alkyl; R₇₀ and R₇₁ are each independently a hydrogen; a (C₁-C₆)alkyl which is unsubstituted or substituted by a hydroxyl or a (C₁-C₃)alkoxy; an ω-HO--(C₁ -C₆)alkyl; an ω--(C₁ -C₃)alkoxy-(C₁ -C₆)alkyl;an ω-phenyl-(C₁ -C₆)alkyl; an ω-R₇₆ OOC--(C₁ -C₆)alkyl; or an ω-R₇₇ R₇₈NCO--(C₁ -C₆)alkyl; or R₇₀ and R₇₁, together with the nitrogen atom towhich they are bonded, form a heterocycle selected from pyrrolidine,piperidine, morpholine, thiomorpholine (or its S-oxide) and piperazinewhich is unsubstituted or substituted in the 4-position by a methylgroup or an ethyl group; R₇₂ and R₇₃ are each independently a (C₁-C₃)alkyl; or R₇₂ and R₇₃ together form a divalent hydrocarbon radicalselected from an ethylene and a trimethylene; R₇₄ is a hydrogen or a (C₁-C₆)alkyl; R₇₅ is a hydrogen or a (C₁ -C₆)alkyl; R₇₆ is a hydrogen or a(C₁ -C₃)alkyl; and R₇₇ and R₇₈ are each independently a hydrogen or a(C₁ -C₃)alkyl; viii--or a group B₁₀ of the formula ##STR156## in whichJ₆ is: a group ##STR157## in which: X₁ is as defined above for the groupB₁, X₁ being other than hydrogen when W₂₅ is a (C₁ -C₇)alkyl or a (C₃-C₇)cycloalkyl; W₂₅ is a (C₁ -C₇)alkyl or a (C₃ -C₇)cycloalkyl; W₂₅ canalso be a group --NR₇₉ R₈₀ when X₁ is a hydrogen, a cyano, a carboxyl, a(C₁ -C₇)alkoxycarbonyl or a group --CONR₁₉ R₂₀ ; and R₇₉ and R₈₀ areeach independently a (C₁ -C₇)alkyl; or R₇₉ and R₈₀, together with thenitrogen atom to which they are bonded, form a heterocycle selected fromazetidine, pyrrolidine, piperidine, morpholine, thio-morpholine andperhydroazepine, with the proviso that:1/ when simultaneously: R₂ is amethyl group or R₁ and R₂ together form a group --(CH₂)₃ --; Ar₁ is a3,4-dichlorophenyl; T is a group --CH₂ --; a group --CO--; a group--COO--; or a group --CONR₃ ; A is a direct bond; a group --(CH₂)_(t) --in which t is one, two or three; or a vinylene group; or --T--A-- is thegroup --SO₂ --; and Z is a phenyl which is unsubstituted ormonosubstituted or polysubstituted by a halogen, a (C₁ -C₄)alkyl, a (C₁-C₄)alkoxy or a nitro, then B is a group B₁ of the formula ##STR158## inwhich J₁ is a group ##STR159## in which: x is zero; Ar₂ is a pyrid-2-ylor a phenyl which is unsubstituted or substituted by a halogen, a methylor a (C₁ -C₄)alkoxy; and X₁ is other than a group selected from:formyl;(C₁ -C₆)alkylcarbonyl; --(CH₂)_(m) --OR₄ in which m is zero or one andR₄ is a hydrogen or a (C₁ -C₇)alkyl; --(CH₂)_(m) --OCOR₅ in which m iszero or one and R₅ is a hydrogen or a (C₁ -C₆)alkyl; --(CH₂)_(m)--OCONH(C₁ -C₇)alkyl in which m is one; --NR₈ R₉ in which R₈ and R₉ areeach independently a hydrogen or a (C₁ -C₇)alkyl; R₉ can also be a (C₃-C₇)cycloalkylmethyl, a benzyl or a phenyl; or R₈ and R₉, together withthe nitrogen atom to which they are bonded, form a heterocycle selectedfrom azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine andperhydroazepine; --(CH₂)_(p) --NR₁₀ R₁₁ in which p is one and R₁₀ andR₁₁ are each independently a hydrogen or a (C₁ -C₇)alkyl; R₁₁ can alsobe a (C₃ -C₇)cycloalkylmethyl or a benzyl; --NR₁₂ COR₁₃ in which R₁₂ isa hydrogen or a (C₁ -C₄)alkyl and R₁₃ is a hydrogen, a (C₁ -C₇)alkyl, aphenyl, a benzyl, a pyridyl or a (C₃ -C₇)cycloalkyl which isunsubstituted or substituted by one or more methyls; or R₁₂ and R₁₃together are a group --(CH₂)_(u) -- in which u is three or four;--(CH₂)_(p) --NR₁₄ C(═W₁)R₁₆ in which p is one, W₁ is an oxygen atom,R₁₄ is a hydrogen or a (C₁ -C₄)alkyl and R₁₆ is a hydrogen, a (C₁-C₇)alkyl, a phenyl, a benzyl, a pyridyl or a (C₃ -C₇)cycloalkyl whichis unsubstituted or substituted by one or more methyls; --(CH₂)_(m)--NR₁₄ COOR₁₇ in which m is zero or one, R₁₄ is a hydrogen or a (C₁-C₄)alkyl and R₁₇ is a (C₁ -C₇)alkyl or a phenyl; --(CH₂)_(m) --NR₁₄ SO₂R₁₈ in which m is zero or one, R₁₄ is a hydrogen or a (C₁ -C₄)alkyl andR₁₈ is a (C₁ -C₇)alkyl, an amino which is free or substituted by one ortwo (C₁ -C₇)alkyls, or a phenyl which is unsubstituted ormonosubstituted or polysubstituted by a substituent selected from ahalogen atom, a (C₁ -C₇)alkyl, a trifluoromethyl, a hydroxyl, a (C₁-C₇)alkoxy, a carboxyl, a (C₁ -C₇)alkoxycarbonyl, a (C₁-C₇)alkylcarbonyloxy, a cyano, a nitro and an amino which is free orsubstituted by one or two (C₁ -C₇)alkyls, said substituents beingidentical or different; --(CH₂)_(m) --NR₁₄ C(═W₁)NR₁₉ R₂₀ in which m iszero or one, W₁ is an oxygen atom, R₁₄ is a hydrogen or a (C₁ -C₄)alkyland R₁₉ and R₂₀ are each independently a hydrogen or a (C₁ -C₇)alkyl;R₂₀ can also be a (C₃ -C₇)cycloalkyl, a (C₃ -C₇)cycloalkylmethyl, ahydroxyl, a (C₁ -C₄)alkoxy, a benzyl or a phenyl; or R₁₉ and R₂₀,together with the nitrogen atom to which they are bonded, form aheterocycle selected from azetidine, pyrrolidine, piperidine,morpholine, thiomorpholine and perhydroazepine; --(CH₂)_(n) --COOR₂₁ inwhich n is zero and R₂₁ is a (C₁ -C₇)alkyl; --(CH₂)_(n) --C(═W₁)NR₁₉ R₂₀in which n is zero, W₁ is an oxygen atom and R₁₉ and R₂₀ are as definedabove; and --CN; or X₁ does not form a double bond between the carbonatom to which it is bonded and the adjacent carbon atom of thepiperidine ring; or Ar₂ and X₁, together with the carbon atom to whichthey are bonded, are other than a group of the formula ##STR160## 2/when R₁ is hydrogen, R₂ is the methyl group, Ar₁ is the3,4-dichlorophenyl group and T--A--Z is the thenoyl group, then B is thegroup B₁ in which J₁ is the group ##STR161## in which x is one, Ar₂ isthe phenyl group and X₁ is other than hydrogen; 3/ when R₁ is hydrogen,R₂ is the methyl group, Ar₁ is the 3,4-dichlorophenyl group and T--A--Zis the 2,4-dichlorobenzoyl group, then B is the group B₁ in which J₁ isthe group ##STR162## in which x is one, Ar₂ is the phenyl group and X₁is other than hydrogen; or 4/ when R₁ and R₂ together form a group--(CH₂)₃ --, Ar₁ is the 3,4-dichlorophenyl group and T--A--Z is the2-(3-methoxyphenyl)acetyl group, the B is the group B₁ in which J₁ isthe group ##STR163## in which x is one, Ar₂ is phenyl and X₁ is otherthan hydrogen; and their salts, where appropriate, with mineral ororganic acids.
 2. A compound of formula (I) according to claim 1 inwhich:Z is Z' and is:a phenyl which is unsubstituted or monosubstitutedor polysubstituted by a substituent selected from a halogen atom; atrifluoromethyl; a cyano; a hydroxyl; a nitro; an amino which isunsubstituted or monosubstituted or disubstituted by a (C₁ -C₄)alkyl; abenzylamino; a carboxyl; a (C₁ -C₁₀)alkyl; a (C₃ -C₈)cycloalkyl which isunsubstituted or monosubstituted or polysubstituted by a methyl; a (C₁-C₁₀)alkoxy; a (C₃ -C₈)cycloalkoxy which is unsubstituted ormonosubstituted or polysubstituted by a methyl; a mercapto; a (C₁-C₁₀)alkylthio; a formyloxy; a (C₁ -C₆)alkylcarbonyloxy; a formylamino;a (C₁ -C₆)alkylcarbonylamino; a benzoylamino; a (C₁ -C₄)alkoxycarbonyl;a (C₃ -C₇)cycloalkoxycarbonyl; a carbamoyl which is unsubstituted ormonosubstituted or disubstituted by a (C₁ -C₄)alkyl; a ureido which isunsubstituted or monosubstituted or disubstituted in the 3-position by a(C₁ -C₄)alkyl or a (C₃ -C₇)cycloalkyl; and a(pyrrolidin-1-yl)carbonylamino, said substituents being identical ordifferent; a naphthyl which is unsubstituted or monosubstituted orpolysubstituted by a halogen, a trifluoromethyl, a (C₁ -C₄)alkyl, ahydroxyl or a (C₁ -C₄)alkoxy; or a pyridyl; a thienyl; an indolyl; aquinolyl; a benzothienyl; or an imidazolyl; Ar, is a 3,4-dichlorophenyl;R₁ and R₂ together form a group --(CH₂)₃ --; and B, T and A are asdefined for (I) in claim 1,and its salts with mineral or organic acids.3. A compound of formula (I) according to claim 1 in which:Z is Z.sup.•and is a pyridyl, thiadiazolyl, indolyl, indazolyl, imidazolyl,benzimidazolyl, benzotriazolyl, benzofuranyl, benzothienyl,benzothiazolyl, benzisothiazolyl, quinolyl, isoquinolyl, benzoxazolyl,benzisoxazolyl, benzoxazinyl, benzodioxinyl, isoxazolyl, benzopyranyl,thiazolyl, thienyl, furyl, pyranyl, chromenyl, isobenzofuranyl,pyrrolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl,phthalazinyl, quinazolinyl, acridinyl, isothiazolyl, isochromanyl orchromanyl group,in which one or more double bonds can be hydrogenated,it being possible for said groups to be unsubstituted or optionally tocontain one or more substituents such as an alkyl, phenyl, cyano,hydroxyalkyl, hydroxyl, alkylcarbonylamino, alkoxycarbonyl or thioalkylgroup, in which the alkyl and alkoxy groups are C₁ -C₄ ; R₁ and R₂together form a group --(CH₂)₃ --; Ar₁ is a 3,4-dichlorophenyl; T is agroup --CO--; A is a direct bond; and B is as defined for a compound offormula (I) in claim 1,and its salts with mineral or organic acids.
 4. Acompound according to claim 3 of the formula ##STR164## in which:Z.sup.• is as defined in claim 3; andB.sup.• is a group of the formula##STR165## in which J.sup.• is: i.sup.• --either a group of thestructure ##STR166## in which: W.sup.• is a phenyl or a benzyl and R₁₉and R₂₀ are as defined for a compound of formula (I) in claim 3;orW.sup.• is a group --NR₇₉ R₈₀ in which R₇₉ and R₈₀ are as defined for(I) in claim 3 and R₁₉ and R₂₀ are each hydrogen;and its salts withmineral or organic acids.
 5. A compound according to claim 4 of theformula ##STR167## wherein: B.sup.• is as defined for a compound offormula (I.sup.•) in claim 4; andZ.sup.•• is chosen from pyridyl,thienyl and furyl,and its salts with mineral or organic acids.
 6. Acompound of the formula ##STR168## wherein: Z.sup.•• is chosen from4-pyridyl, 3-pyridyl, 2-pyridyl, 2-thienyl, 3-thienyl, 2-furyl and3-furyl;and its salts with mineral and organic acids.
 7. A compoundaccording to claim 2 of formula (I) in which simultaneously:B is a groupB₃ in which:either W₃ is oxygen, R₂₉ is a (C₁ -C₄)alkyl or atrifluoromethyl and R₂₈ is a (C₁ -C₆)alkyl, especially an ethyl; or W₃is oxygen, R₂₈ is an alkyl or a cyclohexyl and R₂₉ is a methyl; or W₃ isoxygen, R₂₈ is an ethyl and R₂₉ is a methylamino or a dimethylamino; orW₃ is oxygen and R₂₈ and R₂₉ together form a 1,3-propylene, 1,4-butyleneor cis,cis-1,4-butadienyl group; or W₃ is sulfur and R₂₈ and R₂₉together form a 1,4-butylene group; R₁ and R₂ together form a group--(CH₂)₃ --; Ar, is a 3,4-dichlorophenyl; Z=Z' as defined in claim 2;and T and A are as defined above for a compound of formula (I) in claim2,and its salts with mineral or organic acids.
 8. A compound accordingto claim 2 of formula (I) in which simultaneously:B is B₄ in which: W₄is 1-hydroxypropyl, 1-hydroxyethyl, 1-hydroxybutyl, 2-hydroxybut-2-yl,4-hydroxyhept-4-yl, 2-hydroxyethyl, 1-hydroxyiminopropyl (syn or anti),1-methoxyiminopropyl (syn or anti), 2-acetoxyethyl, 2-acetamidoethyl,carboxyl, ethoxycarbonyl or pyrrolidin-1-ylcarbonyl; R₁ and R₂ togetherform a group --(CH₂)₃ --; Ar₁ is a 3,4-dichlorophenyl; Z=Z' as definedin claim 2; and T and A are as defined above for a compound of formula(I) in claim 2,and its salts with mineral or organic acids.
 9. Acompound according to claim 2 of formula (I) in which simultaneously:Bis a group B₅ in which: W₇ is a hydroxyl, W₆ is a hydrogen and W₈ is aphenyl; or W₆ and W₇ are hydrogen and W₈ is selected from the followinggroups: 5-methyl-1,3,4-oxadiazol-2-yl, 4-ethoxycarbonylimidazol-2-yl,2-fluoropyrid-3-yl, 2-methylthiophenyl, 4-methylthiophenyl,2-methylsulfinylphenyl, 4-methylsulfinylphenyl and4-(N-methylcarbamoyl)phenyl; or W₇ is hydrogen and W₆ and W₈, togetherwith the piperidine to which they are bonded, form aspiro[isobenzofuran-1(3H),4'-piperid]-1'-yl group or a3-oxospiro[isobenzofuran-1(3H),4'-piperid]-1'-yl group; R₁ and R₂together form a group --(CH₂)₃ --; Ar₁ is a 3,4-dichlorophenyl; Z=Z' asdefined in claim 2; and T and A are as defined above for a compound offormula (I) in claim 2,and its salts with mineral or organic acids. 10.A compound according to claim 2 of formula (I) in which simultaneously:Bis a group B₆ as defined in claim 2; R₁ and R₂ together form a group--(CH₂)₃ --; Ar₁ is a 3,4-dichlorophenyl; Z=Z' as defined in claim 2;and T and A are as defined above for a compound of formula (I) in claim2,and its salts with mineral or organic acids.
 11. A compound accordingto claim 2 of formula (I) in which simultaneously:B is a group B₈ inwhich: W₁₇ is a direct bond, W₁₈ is an oxo or thioxo group, W₁₉ is anoxy group or a group NH and W₂₀ is an ethylene or trimethylene group; R₁and R₂ together form a group --(CH₂)₃ --; Ar₁ is a 3,4-dichlorophenyl;Z=Z' as defined according to claim 2; and T and A are as defined abovefor (I) for claim 2,and its salts with mineral or organic acids.
 12. Acompound according to claim 2 of formula (I) in which simultaneously:Bis a group B₉ in which: X₂ is a group --COOR₆₈ or a group --C(═W₂₄)NR₇₀R₇₁ and W₂₁, W₂₂ and W₂₃, together with the nitrogen atom, form a2-oxopiperidino group or a 2-oxoperhydropyrimidin-1-yl group; R₁ and R₂together form a group --(CH₂)₃ --; Ar₁ is a 3,4-dichlorophenyl; Z=Z' asdefined in claim 2; and T and A are as defined above for (I) in claim2,and its salts with mineral or organic acids.
 13. A compound accordingto claim 2 of formula (I) in which simultaneously:B is a group B₁₀ asdefined in claim 2; R₁ and R₂ together form a group --(CH₂)₃ --; Ar₁ isa 3,4-dichlorophenyl; Z=Z' as defined in claim 2; and T and A are asdefined above for (I) in claim 2,and its salts with mineral or organicacids.
 14. A compound according to claim 13 of formula (I) in whichsimultaneously:B is a group B₁₀ in which J₆ is a group ##STR169## inwhich: W₂₅ is a piperid-1-yl and X₁ is a hydrogen, or W₂₅ is anazetidin-1-yl, a pyrrolidin-1-yl, a piperid-1-yl, a morpholin-4-yl, athiomorpholin-4-yl or a perhydroazepin-1-yl and X₁ is a carbamoyl;R₁ andR₂ together form a group --(CH₂)₃ --; Ar₁ is a 3,4dichlorophenyl; Z=Z'as defined in claim 13; T is a group --CO--; and A is a direct bond,andits salts with mineral or organic acids.
 15. A compound according toclaim 2 of the formula ##STR170## in which: Ar'₁ is a phenyl which isunsubstituted or monosubstituted or polysubstituted by a substituentselected from a halogen atom, a hydroxyl, a (C₁ -C₄)alkoxy, a (C₁-C₄)alkyl, a trifluoromethyl and a methylenedioxy, said substituentsbeing identical or different;A' is a direct bond or a group --CH₂ --; Z'is as defined in claim 2; and B_(a) is a group B_(1a) of the formula##STR171## in which J_(1a) is a group ##STR172## in which: x is zero;Ar_(2a) is a phenyl which is unsubstituted or monosubstituted orpolysubstituted by a substituent selected from a halogen atom, ahydroxyl, a (C₁ -C₄)alkoxy, a (C₁ -C₄)alkyl, a trifluoromethyl and amethylenedioxy, said substituents being identical or different; andX_(1a) is a group selected from:hydrogen; (C₁ -C₇)alkyl; --(CH₂)_(m)--OR₄ in which m is two and R₄ is a hydrogen or a (C₁ -C₇)alkyl;--(CH₂)_(m) --OCOR₅ in which: m is two and R₅ is a hydrogen; a (C₁-C₇)alkyl; a (C₃ -C₇)cycloalkyl which is unsubstituted or substituted byone or more methyls; a phenyl; or a pyridyl; or m is zero or one and R₅is a (C₃ -C₇)cycloalkyl which is unsubstituted or substituted by one ormore methyls; a phenyl; or a pyridyl; --(CH₂)_(m) --OCONH(C₁ -C₇)alkylin which m is zero or two; --O--CH₂ --CH₂ --OR₆ in which R₆ is ahydrogen; a (C₁ -C₇)alkyl; a formyl; or a (C₁ -C₇)alkylcarbonyl;--(CH₂)_(n) --SR₇ in which n is zero or one and R₇ is a hydrogen or a(C₁ -C₇)alkyl; --CH₂ --S(O)_(j) --(C₁ -C₇)alkyl in which j is one ortwo; --NR₈ R₉ in which R₈ and R₉, together with the nitrogen atom towhich they are bonded, form a piperazine heterocycle which isunsubstituted or substituted in the 4-position by a (C₁ -C₄)alkyl;--(CH₂)_(p) --NR₁₀ R₁₁ in which p is two and R₁₀ and R₁₁ are eachindependently a hydrogen or a (C₁ -C₇)alkyl; R₁₁ can also be a (C₃-C₇)cycloalkylmethyl or a benzyl; --NR₁₂ COR₁₃ in which R₁₂ is ahydrogen or a (C₁ -C₇)alkyl and R₁₃ is a vinyl, a fryl, a thienyl, apyrrolyl or an imidazolyl; --NR₁₄ COCOR₁₅ in which R₁₄ is a hydrogen ora (C₁ -C₇)alkyl and R₁₅ is a (C₁ -C₄)alkoxy; --(CH₂)_(p) --NR₁₄C(═W₁)R₁₆ in which p is two, W₁ is an oxygen atom or a sulfur atom, R₁₄is a hydrogen or a (C₁ -C₇)alkyl and R₁₆ is a hydrogen; a (C₁ -C₇)alkyl;a (C₃ -C₇)cycloalkyl which is unsubstituted or substituted by one ormore methyls; a phenyl; a benzyl; a vinyl; a pyridyl; a furyl; athienyl; a pyrrolyl; or an imidazolyl; or p is one, W₁ is a sulfur atomand R₁₄ and R₁₆ are as just defined, or W₁ is an oxygen atom, R₁₄ is asjust defined and R₁₆ is a vinyl, a furyl, a thienyl, a pyrrolyl or animidazolyl; --(CH₂)_(m) --NR₁₄ COOR₁₇ in which m is two, R₁₄ is ahydrogen or a (C₁ -C₇)alkyl and R₁₇ is a (C₁ -C₇)alkyl or a phenyl;--(CH₂)_(m) --NR₁₄ SO₂ R₁₈ in which m is two, R₁₄ is a hydrogen or a (C₁-C₇)alkyl and R₁₈ is a (C₁ -C₇)alkyl; an amino which is free orsubstituted by one or two (C₁ -C₇)alkyls; or a phenyl which isunsubstituted or monosubstituted or polysubstituted by a substituentselected from a halogen atom, a (C₁ -C₇)alkyl, a trifluoromethyl, ahydroxyl, a (C₁ -C₇)alkoxy, a carboxyl, a (C₁ -C₇)alkylcarbonyloxy, acyano, a nitro and an amino which is free or substituted by one or two(C₁ -C₇)alkyls, said substituents being identical or different;--(CH₂)_(m) --NR₁₄ C(═W₁)NR₁₉ R₂₀ in which m is two, W₁ is an oxygenatom or a sulfur atom, R₁₄ is a hydrogen or a (C₁ -C₇)alkyl and R₁₉ andR₂₀ are each independently a hydrogen or a (C₁ -C₇)alkyl; R₂₀ can alsobe a (C₃ -C₇)cycloalkyl; a (C₃ -C₇)cycloalkylmethyl; a hydroxyl; a (C₁-C₄)alkoxy; a benzyl; a phenyl; or a (C₁ -C₇)alkyl substituted by ahydroxyl, a (C₁ -C₃)alkoxy, a phenyl, a carboxyl, a (C₁-C₃)alkoxycarbonyl or a carbamoyl which is unsubstituted or substitutedby one or two (C₁ -C₇)alkyls; or R₁₉ and R₂₀, together with the nitrogenatom to which they are bonded, form a heterocycle selected fromazetidine, pyrrolidine, piperidine, morpholine, thiomorpholine,perhydroazepine and piperazine which is unsubstituted or substituted inthe 4-position by a (C₁ -C₄)alkyl; or m is zero or one, W₁ is a sulfturatom and R₁₄, R₁₉ and R₂₀ are as just defined, or W₁ is an oxygen atom,R₁₄ and R₁₉ are each independently a hydrogen or a (C₁ -C₇)alkyl and R₂₀is a (C₁ -C₇)alkyl substituted by a hydroxyl, a (C₁ -C₃)alkoxy, aphenyl, a carboxyl, a (C₁ -C₃)alkoxycarbonyl or a carbamoyl which isunsubstituted or substituted by one or two (C₁ -C₇)alkyls; or R₁₉ andR₂₀, together with the nitrogen atom to which they are bonded, form apiperazine heterocycle which is unsubstituted or substituted in the4-position by a (C₁ -C₄)alkyl; --(CH₂)_(n) --COOR₂₁ in which n is oneand R₂₁ is a hydrogen or a (C₁ -C₇)alkyl; or n is zero and R₂, is ahydrogen; --(CH₂)_(n) --C(═W₁)NR₁₉ R₂₀ in which n is one, W₁ is anoxygen atom or a sulfur atom and R₁₉ and R₂₀ are each independently ahydrogen or a (C₁ -C₇)alkyl; R₂₀ can also be a (C₃ -C₇)cycloalkyl; a (C₃-C₇)cycloalkylmethyl; a hydroxyl; a (C₁ -C₄)alkoxy; a benzyl; a phenyl;or a (C₁ -C₇)alkyl substituted by a hydroxyl, a (C₁ -C₃)alkoxy, aphenyl, a carboxyl, a (C₁ -C₃)alkoxycarbonyl or a carbamoyl which isunsubstituted or substituted by one or two (C₁ -C₇)alkyls; or R₁₉ andR₂₀, together with the nitrogen atom to which they are bonded, form aheterocycle selected from azetidine, pyrrolidine, piperidine,morpholine, thiomorpholine, perhydroazepine and piperazine which isunsubstituted or substituted in the 4-position by a (C₁ -C₄)alkyl; or nis zero, W₁ is a sulfur atom and R₁₉ and R₂₀ are as just defined, or W₁is an oxygen atom, R₁₉ is a hydrogen or a (C₁ -C₇)alkyl and R₂₀ is a (C₁-C₇)alkyl substituted by a hydroxyl, a (C₁ -C₃)alkoxy, a phenyl, acarboxyl, a (C₁ -C₃)alkoxycarbonyl or a carbamoyl which is unsubstitutedor substituted by one or two (C₁ -C₇)alkyls; or R₁₉ and R₂₀, togetherwith the nitrogen atom to which they are bonded, form a piperazineheterocycle which is unsubstituted or substituted in the 4-position by a(C₁ -C₄)alkyl; --CO--NR₂₂ NR₂₃ R₂₄ in which R₂₂ is a hydrogen or a (C₁-C₇)alkyl and R₂₃ and R₂₄ are each independently a hydrogen or a (C₁-C₇)alkyl; ##STR173## in which R₂₅ is a hydrogen or a (C₁ -C₇)alkyl andR₂₆ and R₂₇ are each independently a hydrogen or a (C₁ -C₇)alkyl; R₂₇can also be a formyl or a (C₁ -C₇)alkylcarbonyl; and ##STR174## and itssalts with mineral or organic acids.
 16. A compound according to claim15 of the formula ##STR175## in which: B'_(a) is a group B'_(1a) of theformula ##STR176## in which J '_(1a) is a group ##STR177## in which: xis zero; Ar_(2a) is as defined for a compound of formula (Ia) in claim15; and X'_(1a) is a group selected from:--O--CH₂ --CH₂ --OR₆ in whichR₆ is a hydrogen; a (C₁ -C₇)alkyl; a formyl; or a (C₁ -C₇)alkylcarbonyl;--NR₁₂ COR₁₃ in which R₁₂ is a hydrogen or a (C₁ -C₇)alkyl and R₁₃ is avinyl, a furyl, a thienyl, a pyrrolyl or an imidazolyl; --NR₁₄ COCOR₁₅in which R₁₄ is a hydrogen or a (C₁ -C₇)alkyl and R₁₅ is a (C₁-C₄)alkoxy; --(CH₂)_(p) --NR₁₄ C(═W₁)R₁₆ in which p is one, W₁ is anoxygen atom, R₁₄ is a hydrogen or a (C₁ -C₇)alkyl and R₁₆ is a vinyl, afuryl, a thienyl, a pyrrolyl or an imidazolyl; --(CH₂)_(m) --NR₁₄C(═W₁)NR₁₉ R₂₀ in which m is zero, W₁ is an oxygen atom, R₁₄ is ahydrogen or a (C₁ -C₇)alkyl, R₁₉ is a hydrogen or a (C₁ -C₇)alkyl andR₂₀ is a (C₁ -C₇)alkyl substituted by a hydroxyl, a (C₁ -C₃)alkoxy, aphenyl, a carboxyl, a (C₁ -C₃)alkoxycarbonyl or a carbamoyl which isunsubstituted or substituted by one or two (C₁ -C₇)alkyls; --CO--NR₂₂--NR₂₃ R₂₄ in which R₂₂ is a hydrogen or a (C₁ -C₇)alkyl and R₂₃ and R₂₄are each independently a hydrogen or a (C₁ -C₇)alkyl; ##STR178## inwhich R₂₅ is a hydrogen or a (C₁ -C₇)alkyl and R₂₆ and R₂₇ are eachindependently a hydrogen or a (C₁ -C₇)alkyl; R₂₇ can also be a formyl ora (C₁ -C₇)alkylcarbonyl; and ##STR179## and its salts with mineral ororganic acids.
 17. A compound according to claim 16 of the formula##STR180## in which: X"_(1a) is a group selected from:--O--CH₂ --CH₂--OR₆ in which R₆ is a hydrogen; a (C₁ -C₇)alkyl; a formyl; or a (C₁-C₇)alkylcarbonyl, preferably a hydrogen or an acetyl; --NR₁₂ COR₁₃ inwhich R₁₂ is a hydrogen or a (C₁ -C₇)alkyl, preferably a hydrogen, andR₁₃ is a vinyl, a furyl, a thienyl, a pyrrolyl or an imidazolyl,preferably a furyl or a thienyl; --NR₁₄ COCOR₁₅ in which R₁₄ is ahydrogen or a (C₁ -C₇)alkyl, preferably a hydrogen, and R₁₅ is a (C₁-C₄)alkoxy, preferably an ethoxy; and ##STR181## in which R₂₅ is ahydrogen or a (C₁ -C₇)alkyl, preferably a hydrogen, and R₂₆ and R₂₇ areeach independently a hydrogen or a (C₁ -C₇)alkyl; R₂₇ can also be aformyl or a (C₁ -C₇)alkylcarbonyl; R₂₆ and R₂₇ are preferably ahydrogen; and ##STR182## and its salts with mineral or organic acids.18. A compound according to claim 2 of the formula ##STR183## in which:Ar'₁ is a phenyl which is unsubstituted or monosubstituted orpolysubstituted by a substituent selected from a halogen atom, ahydroxyl, a (C₁ -C₄)alkoxy, a (C₁ -C₄)alkyl, a trifluoromethyl and amethylenedioxy, said substituents being identical or different;A' is adirect bond or a group --CH₂ --; Z' is as defined in claim 2; and B_(b)is a group B_(1b) of the formula ##STR184## in which J_(1b) is a group##STR185## in which: x is one; Ar_(2a) is a phenyl which isunsubstituted or monosubstituted or polysubstituted by a substituentselected from a halogen atom, a hydroxyl, a (C₁ -C₄)alkoxy, a (C₁-C₄)alkyl, a trifluoromethyl and a methylenedioxy, said substituentsbeing identical or different; and X_(1b) is a group selectedfrom:hydrogen (C₁ -C₇)alkyl; formyl; (C₁ -C₇)alkylcarbonyl; --(CH₂)_(m)--OR₄ ; --(CH₂)_(m) --OCOR₅ ; --(CH₂)_(m) --OCONH--(C₁ -C₇)alkyl;--O--CH₂ CH₂ --OR₆ ; --(CH₂)_(n) --SR₇ ; --CH₂ --S(O)_(j) --(C₁-C₇)alkyl; --NR₈ R₉ ; --(CH₂)_(p) --NR₁₀ R₁₁ ; --NR₁₂ COR₁₃ ; --NR₁₄COCOR₁₅ ; --(CH₂)_(p) --NR₁₄ C(═W₁)R₁₆ ; --(CH₂)_(m) --NR₁₄ COOR₁₇ ;--(CH₂)_(m) --NR₁₄ SO₂ R₁₈ ; --(CH₂)_(m) --NR₁₄ C(═W₁)NR₁₉ R₂₀ ;--(CH₂)_(n) --COOR₂₁ ; --(CH₂)_(n) --C(═W₁)NR₁₉ R₂₀ ; --CO--NR₂₂ --NR₂₃R₂₄ ; --CN; ##STR186## or X_(1b) forms a double bond between the carbonatom to which it is bonded and the adjacent carbon atom of thepiperidine ring, in which groups: m is zero, one or two; n is zero orone; p is one or two; j is one or two; W₁ is an oxygen atom or a sulfuratom; R₄ is a hydrogen or a (C₁ -C₇)alkyl;R₅ is a hydrogen; a (C₁-C₇)alkyl; a (C₃ -C₇)cycloalkyl which is unsubstituted or substituted byone or more methyls; a phenyl; or a pyridyl; R₆ is a hydrogen; a (C₁-C₇)alkyl; a formyl; or a (C₁ -C₇)alkylcarbonyl; R₇ is a hydrogen or a(C₁ -C₇)alkyl; R₈ and R₉ are each independently a hydrogen or a (C₁-C₇)alkyl; R₉ can also be a (C₃ -C₇)cycloalkylmethyl, a benzyl or aphenyl; or R₈ and R₉, together with the nitrogen atom to which they arebonded, form a heterocycle selected from azetidine, pyrrolidine,piperidine, morpholine, thio-morpholine, perhydroazepine and piperazinewhich is unsubstituted or substituted in the 4-position by a (C₁-C₄)alkyl; R₁₀ and R₁₁ are each independently a hydrogen or a (C₁-C₇)alkyl; R₁₁ can also be a (C₃ -C₇)cycloalkylmethyl or a benzyl; R₁₂is a hydrogen or a (C₁ -C₇)alkyl; R₁₃ is a hydrogen; a (C₁ -C₇)alkyl; a(C₃ -C₇)cycloalkyl which is unsubstituted or substituted by one or moremethyls; a phenyl; a benzyl; a vinyl; a pyridyl; a furyl; a thienyl; apyrrolyl; or an imidazolyl; or R₁₂ and R₁₃ together are a group--(CH₂)_(u) -- in which u is three or four; R₁₄ is a hydrogen or a (C₁-C₇)alkyl; R₁₅ is a (C₁ -C₄)alkoxy; R₁₆ is a hydrogen; a (C₁ -C₇)alkyl;a (C₃ -C₇)cycloalkyl which is unsubstituted or substituted by one ormore methyls; a phenyl; a benzyl; a vinyl; a pyridyl; a furyl; athienyl; a pyrrolyl; or an imidazolyl; R₁₇ is a (C₁ -C₇)alkyl or aphenyl; R₁₈ is a (C₁ -C₇)alkyl; an amino which is free or substituted byone or two (C₁ -C₇)alkyls; or a phenyl which is unsubstituted ormonosubstituted or polysubstituted by a substituent selected from ahalogen atom, a (C₁ -C₇)alkyl, a trifluoromethyl, a hydroxyl, a (C₁-C₇)alkoxy, a carboxyl, a (C₁ -C₇)alkoxycarbonyl, a (C₁-C₇)alkylcarbonyloxy, a cyano, a nitro and an amino which is free orsubstituted by one or two (C₁ -C₇)alkyls, said substituents beingidentical or different; R₁₉ and R₂₀ are each independently a hydrogen ora (C₁ -C₇)alkyl; R₂₀ can also be a (C₃ -C₇)cycloalkyl; a (C₃-C₇)cycloalkylmethyl; a hydroxyl; a (C₁ -C₄)alkoxy; a benzyl; a phenyl;or a (C₁ -C₇)alkyl substituted by a hydroxyl, a (C₁ -C₃)alkoxy, aphenyl, a carboxyl, a (C₁ -C₃)alkoxycarbonyl or a carbamoyl which isunsubstituted or substituted by one or two (C₁ -C₇)alkyls; or R₁₉ andR₂₀, together with the nitrogen atom to which they are bonded, form aheterocycle selected from azetidine, pyrrolidine, piperidine,morpholine, thio-morpholine, perhydroazepine and piperazine which isunsubstituted or substituted in the 4-position by a (C₁ -C₄)alkyl; R₂,is a hydrogen or a (C₁ -C₇)alkyl; R₂₂ is a hydrogen or a (C₁ -C₇)alkyl;R₂₃ and R₂₄ are each independently a hydrogen or a (C₁ -C₇)alkyl; R₂₅ isa hydrogen or a (C₁ -C₇)alkyl; and R₂₆ and R₂₇ are each independently ahydrogen or a (C₁ -C₇)alkyl; R₂₇ can also be a formyl or a (C₁-C₇)alkylcarbonyl, with the proviso that: when Ar'₁ is the3,4-dichlorophenyl group and --A'--Z' is the 3-methoxybenzyl group,B_(b) is the group B_(1b) of the formula ##STR187## which J_(1b) is thegroup ##STR188## in which x is one, Ar_(2a) is a phenyl group and X_(1b)is other than hydrogen, and its salts with mineral or organic acids. 19.A compound according to claim 18 of the formula ##STR189## in which:B'_(b) is a group B'_(1b) of the formula ##STR190## in which J'_(1b) isa group ##STR191## in which: x is one; Ar_(2a) is a phenyl which isunsubstituted or monosubstituted or polysubstituted by a substituentselected from a halogen atom, a hydroxyl, a (C₁ -C₄)alkoxy, a (C₁-C₄)alkyl, a trifluoromethyl and a methylenedioxy, said substituentsbeing identical or different; and X'_(1b) is as group selected from:(C₁-C₇)alkyl; --(CH₂)_(m) --OR₄ in which m is one or two and R₄ is ahydrogen or a (C₁ -C₇)alkyl; --(CH₂)_(m) --OCOR₅ in which: m is zero andR₅ is a (C₃ -C₇)cycloalkyl which is unsubstituted or substituted by oneor more methyls; a phenyl; or a pyridyl; or m is one or two and R₅ is ahydrogen; a (C₁ -C₇)alkyl; a (C₃ -C₇)cycloalkyl which is unsubstitutedor substituted by one or more methyls; a phenyl; or a pyridyl;--(CH₂)_(m) --OCONH--(C₁ -C₇)alkyln which m is zero, one or two;--O--CH₂ --CH₂ --OR₆ in which R₆ is a hydrogen; a (C₁ -C₇)alkyl; aformyl; or a (C₁ -C₇)alkylcarbonyl; --(CH₂)_(n) --SR₇ in which n is zeroor one and R₇ is a hydrogen or a (C₁ -C₇)alkyl; --CH₂ --S(O)_(j) --(C₁-C₇)alkyln which j is one or two; --NR₈ R₉ in which R₈ is a hydrogen ora (C₁ -C₇)alkyl and R₉ is a (C₃ -C₇)cycloalkylmethyl or a benzyl; or R₈and R₉, together with the nitrogen atom to which they are bonded, form aheterocycle selected from azetidine, thiomorpholine, perhydroazepine andpiperazine which is unsubstituted or substituted in the 4-position by a(C₁ -C₄)alkyl; --(CH₂)_(p) --NR₁₀ R₁₁ in which p is one or two and R₁₀and R₁₁ are each independently a hydrogen or a (C₁ -C₇)alkyl; R₁₁ canalso be a (C₃ -C₇)cycloalkylmethyl or a benzyl; --NR₁₂ COR₁₃ in whichR₁₂ is a hydrogen or a (C₁ -C₇)alkyl and R₁₃ is a (C₃ -C₇)-cycloalkylwhich is unsubstituted or substituted by one or more methyls; a phenyl;a benzyl; a vinyl; a pyridyl; a furyl; a thienyl; a pyrrolyl; or animidazolyl; or R₁₂ and R₁₃ together are a group --(CH₂)_(u) -- in whichu is three or four; --NR₁₄ COCOR₁₅ in which R₁₄ is a hydrogen or a (C₁-C₇)alkyl and R₁₅ is a (C₁ -C₄)alkoxy; --(CH₂)_(p) --NR₁₄ C(═W₁)R₁₆ inwhich p is one or two, W₁ is an oxygen atom or a sulfur atom, R₁₄ is ahydrogen or a (C₁ -C₇)alkyl and R₁₆ is a hydrogen; a (C₁ -C₇)alkyl; a(C₃ -C₇)cycloalkyl which is unsubstituted or substituted by one or moremethyls; a phenyl; a benzyl; a vinyl; a pyridyl; a firyl; a thienyl; apyrrolyl; or an imidazolyl; --(CH₂)_(m) --NR₁₄ COOR₁₇ in which m iszero, one or two, R₁₄ is a hydrogen or a (C₁ -C₇)alkyl and R₁₇ is a (C₁-C₇)alkyl or a phenyl; --(CH₂)_(m) --NR₁₄ SO₂ R₁₈ in which m is zero,one or two, R₁₄ is a hydrogen or a (C₁ -C₇)alkyl and R₁₈ is a (C₁-C₇)alkyl; an amino which is free or substituted by one or two (C₁-C₇)alkyls; or a phenyl which is unsubstituted or monosubstituted orpolysubstituted by a substituent selected from a halogen atom, a (C₁-C₇)alkyl, a trifluoromethyl, a hydroxyl, a (C₁ -C₇)alkoxy, a carboxyl,a (C₁ -C₇)alkoxycarbonyl, a (C₁ -C₇)alkylcarbonyloxy, a cyano, a nitroand an amino which is free or substituted by one or two (C₁ -C₇)alkyls,said substituents being identical or different; --(CH₂)_(m) NR₁₄C(═W₁)NR₁₉ R₂₀ in which m is zero, one or two, W₁ is an oxygen atom or asulfur atom, R₁₄ is a hydrogen or a (C₁ -C₇)alkyl and R₁₉ and R₂₀ areeach independently a hydrogen or a (C₁ -C₇)alkyl; R₂₀ can also be a (C₃-C₇)cycloalkyl; a (C₃ -C₇)cycloalkylmethyl; a hydroxyl; a (C₁-C₄)alkoxy; a benzyl; a phenyl; or a (C₁ -C₇)alkyl substituted by ahydroxyl, a (C₁ -C₃)alkoxy, a phenyl, a carboxyl, a (C₁-C₃)alkoxycarbonyl or a carbamoyl which is unsubstituted or substitutedby one or two (C₁ -C₇)alkyls; or R₁₉ and R₂₀, together with the nitrogenatom to which they are bonded, form a heterocycle selected fromazetidine, pyrrolidine, piperidine, morpholine, thiomorpholine,perhydroazepine and piperazine which is unsubstituted or substituted inthe 4-position by a (C₁ -C₄)alkyl; --(CH₂)_(n) --COOR₂₁ in which n isone and R₂, is a hydrogen or a (C₁ -C₇)alkyl; --(CH₂)_(n) --C(═W₁)NR₁₉R₂₀ in which n is zero or one, W₁ is an oxygen atom or a sulfur atom andR₁₉ and R₂₀ are each independently a hydrogen or a (C₁ -C₇)alkyl; R₂₀can also be a (C₃ -C₇)cycloalkyl; a (C₃ -C₇)cycloalkylmethyl; ahydroxyl; a (C₁ -C₄)alkoxy; a benzyl; a phenyl; or a (C₁ -C₇)alkylsubstituted by a hydroxyl, a (C₁ -C₃)alkoxy, a phenyl, a carboxyl, a (C₁-C₃)alkoxycarbonyl or a carbamoyl which is unsubstituted or substitutedby one or two (C₁ -C₇)alkyls; or R₁₉ and R₂₀, together with the nitrogenatom to which they are bonded, form a heterocycle selected fromazetidine, pyrrolidine, piperidine, morpholine, thiomorpholine,perhydroazepine and piperazine which is unsubstituted or substituted inthe 4-position by a (C₁ -C₄)alkyl; --CO--NR₂₂ --NR₂₃ R₂₄ in which R₂₂ isa hydrogen or a (C₁ -C₇)alkyl and R₂₃ and R₂₄ are each independently ahydrogen or a (C₁ -C₇)alkyl; ##STR192## in which R₂₅ is a hydrogen or a(C₁ -C₇)alkyl and R₂₆ and R₂₇ are each independently a hydrogen or a (C₁-C₇)alkyl; R₂₇ can also be a formyl or a (C₁ -C₇)alkylcarbonyl; and##STR193## and its salts with mineral or organic acids.
 20. A compoundaccording to claim 19 of the formula ##STR194## in which: X"_(1b) is agroup selected from:--(CH₂)_(p) --NR₁₀ R₁₁ in which p is one and R₁₀ andR₁₁ are each a hydrogen; --(CH₂)_(p) --NR₁₄ C(═W₁)R₁₆ in which p is one,W₁ is an oxygen atom, R₁₄ is a hydrogen or a (C₁ -C₇)alkyl and R₁₆ is a(C₁ -C₇)alkyl, preferably an ethyl; --(CH₂)_(m) --NR₁₄ COOR₁₇ in which mis zero, R₁₄ is a hydrogen and R₁₇ is a (C₁ -C₇)alkyl, preferably anethyl; and --(CH₂)_(n) --C(═W₁)NR₁₉ R₂₀ in which n is zero, W₁ is anoxygen atom and R₁₉ and R₂₀, together with the nitrogen atom to whichthey are bonded, form a heterocycle selected from azetidine,pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine andpiperazine which is unsubstituted or substituted in the 4-position by a(C₁ -C₄)alkyl, preferably pyrrolidine,and its salts with mineral ororganic acids.
 21. A compound according to claim 1 selectedfrom:1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(pyrrolidin-1-ylcarbonyl)-piperid-1-yl]propyl]piperidine;1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-(4-piperidinopiperid-1-yl)-propyl]piperidine;1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-(4-carbamoyl-4-piperidinopiperid-1-yl)propyl]piperidine;3-[3-[4-(acryloyl-N-methylamino)-4-phenylpiperid-1-yl]propyl-1-benzoyl-3-(3,4-dichlorophenyl)piperidine;3-[3-[4-(2-aminothiazol-4-yl)-4-phenylpiperid-1-yl]propyl]-1-benzoyl-3-(3,4-dichlorophenyl)piperidine;3-[3-(4-acetyl-4-benzylpiperid-1-yl)propyl]-1-benzoyl-3-(3,4-dichlorophenyl)piperidine;3-[3-[4-(acetylamino)-4-benzylpiperid-1-yl]propyl]-1-benzoyl-3-(3,4-dichlorophenyl)piperidine;1-benzoyl-3-[3-[4-benzyl-4-(propionylaminomethyl)piperid-1-yl]propyl]-3-(3,4-dichlorophenyl)piperidine;1-benzoyl-3-[3-[4-benzyl-4-(ethoxycarbonylamino)piperid-1-yl]propyl]-3-(3,4-dichlorophenyl)piperidine;1-benzoyl-3-[3-[4-benzyl-4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]-3-(3,4-dichlorophenyl)piperidine;1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(2-hydroxyethoxy)-4-phenylpiperid-1-yl]propyl]piperidine;3-[3-[4-(2-acetoxyethoxy)-4-phenylpiperid-1-yl]propyl]-1-benzoyl-3-(3,4-dichlorophenyl)piperidine;1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(2-furoylamino)-4-phenylpiperid-1-yl]propyl]piperidine;1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(2-thenoylamino)-4-phenylpiperid-1-yl]propyl]piperidine;3-(3,4-dichlorophenyl)-1-isonicotinoyl-3-[3-[4-phenyl-4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]piperidine;1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-spiro(indoline-3,4'-piperid-1'-yl)propyl]piperidine;1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[1-acetylspiro(indoline-3,4'-piperid-1'-yl)]propyl]piperidine;3-(3,4-dichlorophenyl)-3-[3-[4-phenyl-4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]-1-(2-thenoyl)piperidine;3-(3,4-dichlorophenyl)-3-[3-[4-phenyl-4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]-1-(3-thenoyl)piperidine;3-(3,4-dichlorophenyl)-1-(2-furoyl)-3-[3-[4-phenyl-4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]piperidine;3-(3,4-dichlorophenyl)-1-(3-furoyl)-3-[3-[4-phenyl-4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]piperidine;3-[3-[4-(2-amino-1,3,4-oxadiazol-5-yl)-4-phenylpiperid-1-yl]propyl]-1-benzoyl-3-(3,4-dichlorophenyl)piperidine;1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(ethoxalylamino)-4-phenylpiperid-1-yl]propyl]piperidine;1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-(4-carbamoyl-4-morpholinopiperid-1-yl)propyl]piperidine;1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[1-(methoxycarbonyl)spiro(indoline-3,4'-piperid-1'-yl)]propyl]piperidine;1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[1-(N,N-dimethylcarbamoyl)spiro(indoline-3,4'-piperid-1'-yl)]propyl]piperidine;and1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[1-(methanesulfonyl)spiro(indoline-3,4'-piperid-1'-yl)]propyl]piperidine,inthe form of racemates or one of their (+) or (-) enantiomers, and theirsalts with mineral or organic acids.
 22. Solvates of the compoundsaccording to any one of claims 1 or 21 and their salts.
 23. A method ofpreparing a compound of formula (I) according to claim 1 or its salts,wherein:1) a compound of the formula ##STR195## in which Ar₁, R₁ and R₂are as defined for a compound of formula (I) in claim 1 and E ishydrogen or an O-protecting group, is treated:either with a halogenatedderivative of the formula

    Hal--CH.sub.2 --A--Z                                       (III)

in which Hal is a halogen atom, preferably bromine, and A and Z are asdefined for a compound of formula (I) in claim 1, when it is desired toprepare a compound of formula (I) in which T is a group --CH₂ --; orwith a functional derivative of an acid of the formula

    HO--CO--A--Z                                               (IIIa)

in which A and Z are as defined above, when it is desired to prepare acompound of formula (I) in which T is a group --CO--; or with achloroformate of the formula

    Cl--COO--A--Z                                              (IIIb)

in which A and Z are as defined above, when it is desired to prepare acompound of formula (I) in which T is group --COO--; or with anisocyanate of the formula

    O═C═N--A--Z                                        (IIIc)

in which A and Z are as defined above, when it is desired to prepare acompound of formula (I) in which T is a group --CO--NR₃ -- in which R₃is hydrogen; or with a carbamoyl chloride of the formula ##STR196## inwhich A and Z are as defined above and R'₃ is a (C₁ -C₄)alkyl, when itis desired to prepare a compound of formula (I) in which T is --CONR₃ --in which R₃ is a (C₁ -C₄)alkyl; or with a sulfonyl chloride of theformula

    Cl--SO.sub.2 --Z                                           (IIIe)

in which Z is as defined above, when it is desired to prepare a compoundof formula (I) in which --T--A-- is a group --SO₂ --, to give a compoundof the formula ##STR197## 2) the O-protecting group, if present, isremoved from the compound of formula (IV), by reaction with an acid or abase, to give the alcohol of the formula ##STR198## 3) the alcohol (V)is treated with a compound of the formula

    G--SO.sub.2 --Cl                                           (VI)

in which G is a methyl, phenyl, tolyl or trifluoromethyl group, to givea compound of the formula ##STR199## 4) the compound (VII) is reacted:either with a cyclic secondary amine of the formula ##STR200## in whichJ'₁ is: ##STR201## in which Ar₂ and x are as defined for (I) in claim 1and X'₁ is either X₁ as defined for (I), or a precursor of X₁, it beingunderstood that when X'₁ contains a hydroxyl group or an amino group,these groups can be protected;or a group Ar₂ --CH═C< in which Ar₂ is asdefined for (I) in claim 1;or a group ##STR202## in which Ar₂ is asdefined for (I) in claim 1; or a group ##STR203## in which Ar₂ is asdefined for (I) in claim 1; or a group ##STR204## in which Ar₂, Am₁ andr are as defined for (I) in claim 1; or a group ##STR205## in which Ar₂and W₂ are as defined for (I) in claim 1; or with a cyclic secondaryamine of the formula ##STR206## in which J₃ is as defined above for (I)in claim 1; or with a cyclic secondary amine of the formula ##STR207##in which W₄ is as defined above for (I) in claim 1; or with a cyclicsecondary amine of the formula ##STR208## in which W₆, W₇ and W₈ are asdefined above for (I) in claim 1; or with a cyclic secondary amine ofthe formula ##STR209## in which J₄ is as defined above for (I) in claim1; or with a cyclic secondary amine of the formula ##STR210## in whichW₁₇, W₁₈, W₁₉ and W₂₀ are are as defined above for (I) in claim 1; orwith a cyclic secondary amine of the formula ##STR211## in which J₅ isas defined above for (I) in claim 1; or with a cyclic secondary amine ofthe formula ##STR212## in which J'₆ is a group ##STR213## in which W₂₅is as defined above for (I) and X'₁ is X₁ as defined for (I) in claim 1,or a precursor of X₁, it being understood that when X'₁ contains ahydroxyl group or an amino group, these groups can be protected; and 5)after deprotection of the hydroxyl groups or amino groups, ifappropriate, or conversion of X'₁ to X₁, if appropriate, the resultingproduct is optionally converted to one of its salts with a mineral ororganic acid.
 24. A method of preparing a compound of formula (I)according to claim 1 or its salt, wherein:1) the nitrogen atom of thecompound of formula (II) ##STR214## is protected to give a compound ofthe formula ##STR215## in which Ar₁, R₁ and R₂ are as defined for acompound of formula (I) in claim 1, E is hydrogen or an O-protectinggroup and Pr is an N-protecting group such as the trityl,tert-butoxycarbonyl or benzyloxycarbonyl group; 2) the O-protectinggroup, if present is removed from the compound of formula (XVII), byreaction with an acid or a base, to give the alcohol of the formula##STR216## 3) the alcohol (XVIII) is treated with a compound of formula(VI)

    G--SO.sub.2 --Cl                                           (VI)

in which G is a methyl, phenyl, tolyl or trifluoromethyl group to give acompound of the formula ##STR217## 4) the compound (XIX) is reacted:either with a cyclic secundary amine of the formula ##STR218## in whichJ'₁ is: either a group ##STR219## in which Ar₂ and x are as defined for(I) in claim 1 and X'₁ is either X₁ as defined for (I), or a precursorof X₁, it being understood that when X'₁ contains a hydroxyl group or anamino group, these groups can be protected;or a group ##STR220## inwhich Ar₂ is as defined for (I) in claim 1; or a group ##STR221## inwhich Ar₂ is as defined for (I) in claim 1; or a group ##STR222## inwhich Ar₂ is as defined for (I) in claim 1; or a group ##STR223## inwhich Ar₂, Am₁ and r are as defined for (I) in claim 1; or a group##STR224## in which Ar₂ and W₂ are as defined for (I) in claim 1; orwith a cyclic secondary amine of the formula ##STR225## in which J₃ isas defined above for (I) in claim 1; or with a cyclic secondary amine ofthe formula ##STR226## in which W₄ is as defined above for (I) in claim1; or with a cyclic secondary amine of the formula ##STR227## in whichW₆, W₇ and W₈ are as defined above for (I) in claim 1; or with a cyclicsecondary amine of the formula ##STR228## in which J₄ is as definedabove for (I) in claim 1; or with a cyclic secondary amine of theformula ##STR229## in which W₁₇, W₁₈, W₁₉ and W₂₀ are as defined abovefor (I) in claim 1; or with a cyclic secondary amine of the formula##STR230## in which J₅ is as defined above for (I) in claim 1; or with acompound of the formula ##STR231## in which J'₆ is a group ##STR232## inwhich W₂₅ is as defined above for (I) and X'₁ is X₁ as defined for (I)in claim 1, or a precursor of X₁, it being understood that when X'₁contains a hydroxyl group or an amino group, these groups can beprotected; to give a compound of the formula ##STR233## in which B is asdefined for compound of the formula (I) in claim 1, it being understoodthat when B contains a hydroxyl group or an amino group, these groupscan be protected; 5) the protectiing group Pr is selectively removedfrom the compound of the formula (XX) to give the compound of theformula ##STR234## 6) the compound of formula (XXI) is treated: eitherwith a halogenated derivative of the formula

    Hal--CH.sub.2 --A--Z                                       (III)

in which Hal is a halogen atom, preferably bromine, and A and Z are asdefined for a compound of formula (I) in claim 1, when it is desired toprepare a compound of formula (I) in which T is a group --CH₂ --;or witha functional derivative of an acid of the formula

    HO--CO--A--Z                                               (IIIa)

in which A and Z are as defined above, when it is desired to prepare acompound of formula (I) in which T is group --CO--;or with achoroformate of the formula

    Cl--COO--A--Z                                              (IIIb)

in which A and Z are as defined above, when it is desired to prepare acompound of formula (I) in which T is group --COO--;or with anisocyanate of the formula

    O═C═N--A--Z                                        (IIIc)

in which A and Z are as defined above, when it is desired to prepare acompound of formula (I) in which T is a group --CO--NR₃ -- in which R₃is hydrogen;or with a carbamoyl chloride of the formula ##STR235## inwhich A and Z are as defined above and R'₃ is a (C₁ -C₄)alkyl, when itis desired to prepare a compound of formula (I) in which T is --CONR₃ --in which R₃ is a (C₁ -C₄)alkyl; or with a sulfonyl chloride of theformula

    Cl--SO.sub.2 --Z                                           (IIIe)

in which Z is as defined above, when it is desired to prepare a compoundof formula (I) in which --T--A-- is a group --SO₂ --; and 7) afterdeprotection of the hydroxyl groups or amino groups, if appropriate, theresulting product is optionally converted to one of its salts with amineral or organic acid.
 25. A method for the preparation of a compoundof formula (I*) according to claim 4 or its salts, wherein:1*) acompound of the formula ##STR236## in which G is a methyl, phenyl, tolylor trifluoromethyl group and Pr is an N-protecting group such as thetrityl, tert-butoxycarbonyl or benzyloxycarbonyl group, is reacted witha compound of the formula ##STR237## in which J* is as defined for acompound of formula (I*) in claim 4, to give a compound of the formula##STR238## 2*) the protecting group Pr is selectively removed from thecompound of formula (XX*) to give the compound of the formula ##STR239##3*) the compound of formula (XXI*) is treated with a functionalderivative of an acid of the formula

    HO--CO--Z*                                                 (III*)

in which Z* is as defined for a compound of formula (I*) in claim 4; and4*) a deprotection, if appropriate, the resulting product (I*) isoptionally converted to one of its salts with a mineral or organic acid.26. An enantiomer of a compound according to claim 1 of the formula##STR240## or one of its pharmaceutically acceptable saltsin which: "*"denotes that the carbon atom carrying this label has the determined (+)or (-) absolute configuration; andR₁, R₂, Ar₁, T, A, Z and B are asdefined for the compounds of formula (I) in claim 1, and its salts withmineral or organic acids, and their solvates.
 27. A phamaceuticalcomposition comprising a therapeutically effective amount of a compoundaccording to any one of claims 1, 21 or
 26. 28. A pharmaceuticalcomposition according to claim 27 in the form of a dosage unit in whichsaid effective amount of a compound is mixed with at least onepharmaceutical excipient.
 29. A pharmaceutical composition according toclaim 28 containing 0.5 to 1000 mg of said compound.
 30. A phamaceuticalcomposition according to claim 29 containing 2.5 to 250 mg of saidcompound.
 31. A method for the treatment of diseasesin which the NK₃receptor is involved which comprises administering to a patient in needof such treatment an effective amount of a compound according to any oneof claims 1, 21, or 26.